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Special Issue "Oxidative Stress in Cardiovascular Disease"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology".

Deadline for manuscript submissions: closed (30 May 2013)

Special Issue Editors

Guest Editor
Prof. Dr. Francis J. Miller Jr. (Website)

Departments of Internal Medicine and Anatomy and Cell Biology, University of Iowa, Veterans Affairs Medical Center, Iowa City, Iowa, USA
Interests: atherosclerosis; reactive oxygen species; oxidative stress; smooth muscle cells; NADPH oxidases; restenosis; redox signaling
Guest Editor
Dr. Gabor Csanyi (Website)

Department of Pharmacology and Toxicology, Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA
Interests: oxidative stress, reactive oxygen species, NADPH oxidase, cardiovascular disease, vascular tone dysfunction, thrombospondins, nitric oxide, prostanoids, and EDHF

Special Issue Information

Dear Colleagues,

Cardiovascular disease is the leading cause of mortality and the most expensive health condition in the United States. Animal and human data implicate increased levels of reactive oxygen species (ROS) associated with oxidative stress in the pathogenesis of cardiovascular disease. Whereas ROS are essential for normal cellular processes, the molecular effects of increased ROS include the oxidation of DNA, RNA, lipids and proteins resulting in the dysregulation of ion channels, signaling pathways and transcription factors. However, we still do not have a complete understanding of the underlying mechanisms and consequences of increased ROS generation in cardiovascular tissue. Reducing oxidative stress represents a promising approach for prevention and treatment of cardiovascular disease. However, in numerous clinical trials, antioxidant supplementation failed to reduce cardiovascular morbidity or mortality. Therefore, alternative strategies are to achieve targeted delivery of antioxidants or to inhibit specific enzymatic sources of ROS, which include the mitochondria,  NADPH oxidases, xanthine oxidase, lipooxygenase, cyclooxygenase, and nitric oxide synthase. This special issue will focus on the causes and consequence of oxidative stress in cardiovascular disease and explore emerging treatment strategies.

Prof. Dr. Francis Miller, Jr.
Dr. Gabor Csanyi
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF.

Keywords

  • oxidative stress, reactive oxygen species
  • heart disease, myocardial infarction, ischemia/reperfusion, preconditioning
  • vascular disease, atherosclerosis, hypertension, restenosis, stroke, thrombosis
  • biomarkers of oxidative stress
  • redox-mediated signaling
  • transcription factors, antioxidant response elements
  • antioxidant therapy

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Published Papers (31 papers)

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Editorial

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Open AccessEditorial Oxidative Stress in Cardiovascular Disease
Int. J. Mol. Sci. 2014, 15(4), 6002-6008; doi:10.3390/ijms15046002
Received: 7 March 2014 / Revised: 25 March 2014 / Accepted: 31 March 2014 / Published: 9 April 2014
Cited by 5 | PDF Full-text (161 KB) | HTML Full-text | XML Full-text
Abstract
In the special issue “Oxidative Stress in Cardiovascular Disease” authors were invited to submit papers that investigate key questions in the field of cardiovascular free radical biology. The original research articles included in this issue provide important information regarding novel aspects of [...] Read more.
In the special issue “Oxidative Stress in Cardiovascular Disease” authors were invited to submit papers that investigate key questions in the field of cardiovascular free radical biology. The original research articles included in this issue provide important information regarding novel aspects of reactive oxygen species (ROS)-mediated signaling, which have important implications in physiological and pathophysiological cardiovascular processes. The issue also included a number of review articles that highlight areas of intense research in the fields of free radical biology and cardiovascular medicine. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)

Research

Jump to: Editorial, Review

Open AccessArticle Up-Regulation of mRNA Ventricular PRNP Prion Protein Gene Expression in Air Pollution Highly Exposed Young Urbanites: Endoplasmic Reticulum Stress, Glucose Regulated Protein 78, and Nanosized Particles
Int. J. Mol. Sci. 2013, 14(12), 23471-23491; doi:10.3390/ijms141223471
Received: 5 September 2013 / Revised: 8 November 2013 / Accepted: 13 November 2013 / Published: 28 November 2013
PDF Full-text (448 KB) | HTML Full-text | XML Full-text
Abstract
Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of [...] Read more.
Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Impact of Cold Ischemia on Mitochondrial Function in Porcine Hearts and Blood Vessels
Int. J. Mol. Sci. 2013, 14(11), 22042-22051; doi:10.3390/ijms141122042
Received: 16 August 2013 / Revised: 28 October 2013 / Accepted: 30 October 2013 / Published: 7 November 2013
Cited by 3 | PDF Full-text (231 KB) | HTML Full-text | XML Full-text
Abstract
The effects of cold storage using Custodiol® (Histidine-Tryptophan-Ketoglutarate, HTK) or isotonic saline solution on mitochondrial function in hearts (left and rights ventricles) and various blood vessels of pigs were investigated. Hearts, saphenous veins, internal-mammary-arteries and aortas of male landrace pigs were [...] Read more.
The effects of cold storage using Custodiol® (Histidine-Tryptophan-Ketoglutarate, HTK) or isotonic saline solution on mitochondrial function in hearts (left and rights ventricles) and various blood vessels of pigs were investigated. Hearts, saphenous veins, internal-mammary-arteries and aortas of male landrace pigs were harvested and exposed to cold ischemia in either saline or Custodiol-HTK solution. Mitochondrial function was measured in situ in permeabilized fibers by high-resolution respirometry. Mitochondrial respiratory capacities (maximal respiration rates) were similar in the right and left ventricle in controls and after 14 h of cold storage were significantly better preserved in Custodiol-HTK than in saline solution. Mitochondrial respiration rates in various blood vessels including aorta, arteries and veins were less than 5% of myocardium rates. In contrast to the pig heart, in some blood vessels, like veins, mitochondrial function remained stable even after 24 h of cold ischemia. HTK-Custodiol protection of mitochondrial function after prolonged cold ischemia was observed in the myocardium but not in blood vessels. HTK-Custodiol solution thus offers significant protection of myocardial mitochondria against cold ischemic injury and can be used as efficient preservation solution in organ transplantation but probably has no benefit for blood vessels preservation. Analysis of mitochondrial function can be used as a valuable approach for the assessment of cold ischemic injury in various tissues including pig heart and various blood vessels. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Proteomic Analysis Identifies an NADPH Oxidase 1 (Nox1)-Mediated Role for Actin-Related Protein 2/3 Complex Subunit 2 (ARPC2) in Promoting Smooth Muscle Cell Migration
Int. J. Mol. Sci. 2013, 14(10), 20220-20235; doi:10.3390/ijms141020220
Received: 8 August 2013 / Revised: 28 August 2013 / Accepted: 16 September 2013 / Published: 11 October 2013
Cited by 4 | PDF Full-text (3072 KB) | HTML Full-text | XML Full-text
Abstract
A variety of vascular pathologies, including hypertension, restenosis and atherosclerosis, are characterized by vascular smooth muscle cell (VSMC) hypertrophy and migration. NADPH oxidase 1 (Nox1) plays a pivotal role in these phenotypes via distinct downstream signaling. However, the mediators differentiating these distinct [...] Read more.
A variety of vascular pathologies, including hypertension, restenosis and atherosclerosis, are characterized by vascular smooth muscle cell (VSMC) hypertrophy and migration. NADPH oxidase 1 (Nox1) plays a pivotal role in these phenotypes via distinct downstream signaling. However, the mediators differentiating these distinct phenotypes and their precise role in vascular disease are still not clear. The present study was designed to identify novel targets of VSMC Nox1 signaling using 2D Differential In-Gel Electrophoresis and Mass Spectrometry (2D-DIGE/MS). VSMC treatment with scrambled (Scrmb) or Nox1 siRNA and incubation with the oxidant hydrogen peroxide (H2O2; 50 µM, 3 h) followed by 2D-DIGE/MS on cell lysates identified 10 target proteins. Among these proteins, actin-related protein 2/3 complex subunit 2 (ARPC2) with no previous link to Nox isozymes, H2O2, or other reactive oxygen species (ROS), was identified and postulated to play an intermediary role in VSMC migration. Western blot confirmed that Nox1 mediates H2O2-induced ARPC2 expression in VSMC. Treatment with a p38 MAPK inhibitor (SB203580) resulted in reduced ARPC2 expression in H2O2-treated VSMC. Additionally, wound-healing “scratch” assay confirmed that H2O2 stimulates VSMC migration via Nox1. Importantly, gene silencing of ARPC2 suppressed H2O2-stimulated VSMC migration. These results demonstrate for the first time that Nox1-mediated VSMC migration involves ARPC2 as a downstream signaling target. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Achyranthes bidentata Polypeptides Reduces Oxidative Stress and Exerts Protective Effects against Myocardial Ischemic/Reperfusion Injury in Rats
Int. J. Mol. Sci. 2013, 14(10), 19792-19804; doi:10.3390/ijms141019792
Received: 19 August 2013 / Revised: 16 September 2013 / Accepted: 17 September 2013 / Published: 30 September 2013
Cited by 9 | PDF Full-text (768 KB) | HTML Full-text | XML Full-text
Abstract
Achyranthes bidentata, a Chinese medicinal herb, is reported to be neuroprotective. However, its role in cardioprotection remains largely unknown. Our present study aimed to investigate the effects of Achyranthes bidentata polypeptides (ABPP) preconditioning on myocardial ischemia/reperfusion (MI/R) injury and to test [...] Read more.
Achyranthes bidentata, a Chinese medicinal herb, is reported to be neuroprotective. However, its role in cardioprotection remains largely unknown. Our present study aimed to investigate the effects of Achyranthes bidentata polypeptides (ABPP) preconditioning on myocardial ischemia/reperfusion (MI/R) injury and to test the possible mechanisms. Rats were treated with ABPP (10 mg/kg/d, i.p.) or saline once daily for one week. Afterward, all the animals were subjected to 30 min of myocardial ischemia followed by 4 h of reperfusion. ABPP preconditioning for one week significantly improved cardiac function following MI/R. Meanwhile, ABPP reduced infarct size, plasma creatine kinase (CK)/lactate dehydrogenase (LDH) activities and myocardial apoptosis at the end of reperfusion in rat hearts. Moreover, ABPP preconditioning significantly inhibited superoxide generation, gp91phox expression, malonaldialdehyde formation and enhanced superoxide dismutase activity in I/R hearts. Furthermore, ABPP treatment inhibited PTEN expression and increased Akt phosphorylation in I/R rat heart. PI3K inhibitor wortmannin blocked Akt activation, and abolished ABPP-stimulated anti-oxidant effect and cardioprotection. Our study demonstrated for the first time that ABPP reduces oxidative stress and exerts cardioprotection against MI/R injury in rats. Inhibition of PTEN and activation of Akt may contribute to the anti-oxidant capacity and cardioprotection of ABPP. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Oleic Acid Increases Synthesis and Secretion of VEGF in Rat Vascular Smooth Muscle Cells: Role of Oxidative Stress and Impairment in Obesity
Int. J. Mol. Sci. 2013, 14(9), 18861-18880; doi:10.3390/ijms140918861
Received: 31 May 2013 / Revised: 5 August 2013 / Accepted: 5 September 2013 / Published: 13 September 2013
Cited by 4 | PDF Full-text (1376 KB) | HTML Full-text | XML Full-text
Abstract
Obesity is characterized by poor collateral vessel formation, a process involving vascular endothelial growth factor (VEGF) action on vascular smooth muscle cells (VSMC). Free fatty acids are involved in the pathogenesis of obesity vascular complications, and we have aimed to clarify whether [...] Read more.
Obesity is characterized by poor collateral vessel formation, a process involving vascular endothelial growth factor (VEGF) action on vascular smooth muscle cells (VSMC). Free fatty acids are involved in the pathogenesis of obesity vascular complications, and we have aimed to clarify whether oleic acid (OA) enhances VEGF synthesis/secretion in VSMC, and whether this effect is impaired in obesity. In cultured aortic VSMC from lean and obese Zucker rats (LZR and OZR, respectively) we measured the influence of OA on VEGF-A synthesis/secretion, signaling molecules and reactive oxygen species (ROS). In VSMC from LZR we found the following: (a) OA increases VEGF-A synthesis/secretion by a mechanism blunted by inhibitors of Akt, mTOR, ERK-1/2, PKC-beta, NADPH-oxidase and mitochondrial electron transport chain complex; (b) OA activates the above mentioned signaling pathways and increases ROS; (c) OA-induced activation of PKC-beta enhances oxidative stress, which activates signaling pathways responsible for the increased VEGF synthesis/secretion. In VSMC from OZR, which present enhanced baseline oxidative stress, the above mentioned actions of OA on VEGF-A, signaling pathways and ROS are impaired: this impairment is reproduced in VSMC from LZR by incubation with hydrogen peroxide. Thus, in OZR chronically elevated oxidative stress causes a resistance to the action on VEGF that OA exerts in LZR by increasing ROS. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Redox Signaling Is an Early Event in the Pathogenesis of Renovascular Hypertension
Int. J. Mol. Sci. 2013, 14(9), 18640-18656; doi:10.3390/ijms140918640
Received: 12 August 2013 / Revised: 30 August 2013 / Accepted: 2 September 2013 / Published: 10 September 2013
Cited by 10 | PDF Full-text (2207 KB) | HTML Full-text | XML Full-text
Abstract
Activation of the renin-angiotensin-aldosterone system plays a critical role in the development of chronic renal damage in patients with renovascular hypertension. Although angiotensin II (Ang II) promotes oxidative stress, inflammation, and fibrosis, it is not known how these pathways intersect to produce [...] Read more.
Activation of the renin-angiotensin-aldosterone system plays a critical role in the development of chronic renal damage in patients with renovascular hypertension. Although angiotensin II (Ang II) promotes oxidative stress, inflammation, and fibrosis, it is not known how these pathways intersect to produce chronic renal damage. We tested the hypothesis that renal parenchymal cells are subjected to oxidant stress early in the development of RVH and produce signals that promote influx of inflammatory cells, which may then propagate chronic renal injury. We established a reproducible murine model of RVH by placing a tetrafluoroethhylene cuff on the right renal artery. Three days after cuff placement, renal tissue demonstrates no histologic abnormalities despite up regulation of both pro- and anti-oxidant genes. Mild renal atrophy was observed after seven days and was associated with induction of Tnfα and influx of CD3+ T cells and F4/80+ macrophages. By 28 days, kidneys developed severe renal atrophy with interstitial inflammation and fibrosis, despite normalization of plasma renin activity. Based on these considerations, we propose that renal parenchymal cells initiate a progressive cascade of events leading to oxidative stress, interstitial inflammation, renal fibrosis, and atrophy. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Apigenin Protects Endothelial Cells from Lipopolysaccharide (LPS)-Induced Inflammation by Decreasing Caspase-3 Activation and Modulating Mitochondrial Function
Int. J. Mol. Sci. 2013, 14(9), 17664-17679; doi:10.3390/ijms140917664
Received: 14 June 2013 / Revised: 30 July 2013 / Accepted: 16 August 2013 / Published: 28 August 2013
Cited by 15 | PDF Full-text (513 KB) | HTML Full-text | XML Full-text
Abstract
Acute and chronic inflammation is characterized by increased reactive oxygen species (ROS) production, dysregulation of mitochondrial metabolism and abnormal immune function contributing to cardiovascular diseases and sepsis. Clinical and epidemiological studies suggest potential beneficial effects of dietary interventions in inflammatory diseases but [...] Read more.
Acute and chronic inflammation is characterized by increased reactive oxygen species (ROS) production, dysregulation of mitochondrial metabolism and abnormal immune function contributing to cardiovascular diseases and sepsis. Clinical and epidemiological studies suggest potential beneficial effects of dietary interventions in inflammatory diseases but understanding of how nutrients work remains insufficient. In the present study, we evaluated the effects of apigenin, an anti-inflammatory flavonoid abundantly found in our diet, in endothelial cells during inflammation. Here, we show that apigenin reduced lipopolysaccharide (LPS)-induced apoptosis by decreasing ROS production and the activity of caspase-3 in endothelial cells. Apigenin conferred protection against LPS-induced mitochondrial dysfunction and reestablished normal mitochondrial complex I activity, a major site of electron leakage and superoxide production, suggesting its ability to modulate endothelial cell metabolic function during inflammation. Collectively, these findings indicate that the dietary compound apigenin stabilizes mitochondrial function during inflammation preventing endothelial cell damage and thus provide new translational opportunities for the use of dietary components in the prevention and treatment of inflammatory diseases. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Differential Proinflammatory and Oxidative Stress Response and Vulnerability to Metabolic Syndrome in Habitual High-Fat Young Male Consumers Putatively Predisposed by Their Genetic Background
Int. J. Mol. Sci. 2013, 14(9), 17238-17255; doi:10.3390/ijms140917238
Received: 3 June 2013 / Revised: 12 August 2013 / Accepted: 13 August 2013 / Published: 22 August 2013
Cited by 5 | PDF Full-text (247 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The current nutritional habits and lifestyles of modern societies favor energy overloads and a diminished physical activity, which may produce serious clinical disturbances and excessive weight gain. In order to investigate the mechanisms by which the environmental factors interact with molecular mechanisms [...] Read more.
The current nutritional habits and lifestyles of modern societies favor energy overloads and a diminished physical activity, which may produce serious clinical disturbances and excessive weight gain. In order to investigate the mechanisms by which the environmental factors interact with molecular mechanisms in obesity, a pathway analysis was performed to identify genes differentially expressed in subcutaneous abdominal adipose tissue (SCAAT) from obese compared to lean male (21–35 year-old) subjects living in similar obesogenic conditions: habitual high fat dietary intake and moderate physical activity. Genes involved in inflammation (ALCAM, CTSB, C1S, YKL-40, MIF, SAA2), extracellular matrix remodeling (MMP9, PALLD), angiogenesis (EGFL6, leptin) and oxidative stress (AKR1C3, UCHL1, HSPB7 and NQO1) were upregulated; whereas apoptosis, signal transcription (CITED 2 and NR3C1), cell control and cell cycle-related genes were downregulated. Interestingly, the expression of some of these genes (C1S, SAA2, ALCAM, CTSB, YKL-40 and tenomodulin) was found to be associated with some relevant metabolic syndrome features. The obese group showed a general upregulation in the expression of inflammatory, oxidative stress, extracellular remodeling and angiogenic genes compared to lean subjects, suggesting that a given genetic background in an obesogenic environment could underlie the resistance to gaining weight and obesity-associated manifestations. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Figures

Open AccessArticle Inhibition of NADPH Oxidase by Apocynin Attenuates Progression of Atherosclerosis
Int. J. Mol. Sci. 2013, 14(8), 17017-17028; doi:10.3390/ijms140817017
Received: 27 May 2013 / Revised: 26 July 2013 / Accepted: 9 August 2013 / Published: 19 August 2013
Cited by 18 | PDF Full-text (1073 KB) | HTML Full-text | XML Full-text
Abstract
Of the multiple sources of reactive oxygen species (ROS) in the blood vessel, NADPH oxidases are the primary source. Whereas several studies have implicated NADPH oxidases in the initiation of atherosclerosis, their roles in disease progression are incompletely understood. Our objective was [...] Read more.
Of the multiple sources of reactive oxygen species (ROS) in the blood vessel, NADPH oxidases are the primary source. Whereas several studies have implicated NADPH oxidases in the initiation of atherosclerosis, their roles in disease progression are incompletely understood. Our objective was to determine the potential clinical relevance of inhibiting NADPH oxidase in established atherosclerosis. Using a hypercholesteremic murine model of atherosclerosis (ApoE−/−/LDLR−/− (AS) mice on normal chow diet), we first established a time-dependent relationship between superoxide levels and lesion size in AS mice. Next, we identified NADPH oxidase as the primary source of ROS in atherosclerotic lesions. Treatment of aortic segments from AS mice with apocynin, which interferes with NADPH oxidase activation in part by preventing translocation of the subunit p47phox, significantly reduced superoxide levels. Moreover, addition of apocynin to the drinking water of AS mice produced a decrease in lesion size as compared to untreated AS mice, with the effect most pronounced in the thoracoabdominal aorta but absent from the aortic arch. Granulocyte function in AS+apocynin mice was suppressed, confirming efficacy of apocynin treatment. We conclude that apocynin attenuates the progression of atherosclerosis in hypercholesterolemic mice, potentially by its ability to inhibit generation of superoxide by NADPH oxidase. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Mild Oxidative Damage in the Diabetic Rat Heart Is Attenuated by Glyoxalase-1 Overexpression
Int. J. Mol. Sci. 2013, 14(8), 15724-15739; doi:10.3390/ijms140815724
Received: 27 May 2013 / Revised: 26 June 2013 / Accepted: 8 July 2013 / Published: 29 July 2013
Cited by 8 | PDF Full-text (352 KB) | HTML Full-text | XML Full-text
Abstract
Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs) and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of [...] Read more.
Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs) and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of the current study was to investigate if a reduction of AGEs by overexpression of the glycation precursor detoxifying enzyme glyoxalase-I (GLO-I) can prevent diabetes-induced oxidative damage, inflammation and fibrosis in the heart. Diabetes was induced in wild-type and GLO-I transgenic rats by streptozotocin. After 24-weeks of diabetes, cardiac function was monitored with ultrasound under isoflurane anesthesia. Blood was drawn and heart tissue was collected for further analysis. Analysis with UPLC-MSMS showed that the AGE Nε-(1-carboxymethyl)lysine and its precursor 3-deoxyglucosone were significantly elevated in the diabetic hearts. Markers of oxidative damage, inflammation, and fibrosis were mildly up-regulated in the heart of the diabetic rats and were attenuated by GLO-I overexpression. In this model of diabetes, these processes were not accompanied by significant changes in systolic heart function, i.e., stroke volume, fractional shortening and ejection fraction. This study shows that 24-weeks of diabetes in rats induce early signs of mild cardiac alterations as indicated by an increase of oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle The Role of Sulfur Dioxide in the Regulation of Mitochondrion-Related Cardiomyocyte Apoptosis in Rats with Isopropylarterenol-Induced Myocardial Injury
Int. J. Mol. Sci. 2013, 14(5), 10465-10482; doi:10.3390/ijms140510465
Received: 5 March 2013 / Revised: 24 April 2013 / Accepted: 9 May 2013 / Published: 21 May 2013
Cited by 13 | PDF Full-text (1774 KB) | HTML Full-text | XML Full-text
Abstract
The authors investigated the regulatory effects of sulfur dioxide (SO2) on myocardial injury induced by isopropylarterenol (ISO) hydrochloride and its mechanisms. Wistar rats were divided into four groups: control group, ISO group, ISO plus SO2 group, and SO2 [...] Read more.
The authors investigated the regulatory effects of sulfur dioxide (SO2) on myocardial injury induced by isopropylarterenol (ISO) hydrochloride and its mechanisms. Wistar rats were divided into four groups: control group, ISO group, ISO plus SO2 group, and SO2 only group. Cardiac function was measured and cardiomyocyte apoptosis was detected. Bcl-2, bax and cytochrome c (cytc) expressions, and caspase-9 and caspase-3 activities in the left ventricular tissues were examined in the rats. The opening status of myocardial mitochondrial permeability transition pore (MPTP) and membrane potential were analyzed. The results showed that ISO-treated rats developed heart dysfunction and cardiac injury. Furthermore, cardiomyocyte apoptosis in the left ventricular tissues was augmented, left ventricular tissue bcl-2 expression was down-regulated, bax expression was up-regulated, mitochondrial membrane potential was significantly reduced, MPTP opened, cytc release from mitochondrion into cytoplasm was significantly increased, and both caspase-9 and caspase-3 activities were increased. Administration of an SO2 donor, however, markedly improved heart function and relieved myocardial injury of the ISO-treated rats; it lessened cardiomyocyte apoptosis, up-regulated myocardial bcl-2, down-regulated bax expression, stimulated mitochondrial membrane potential, closed MPTP, and reduced cytc release as well as caspase-9 and caspase-3 activities in the left ventricular tissue. Hence, SO2 attenuated myocardial injury in association with the inhibition of apoptosis in myocardial tissues, and the bcl-2/cytc/caspase-9/caspase-3 pathway was possibly involved in this process. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Native High Density Lipoproteins (HDL) Interfere with Platelet Activation Induced by Oxidized Low Density Lipoproteins (OxLDL)
Int. J. Mol. Sci. 2013, 14(5), 10107-10121; doi:10.3390/ijms140510107
Received: 11 March 2013 / Revised: 16 April 2013 / Accepted: 29 April 2013 / Published: 10 May 2013
Cited by 6 | PDF Full-text (1430 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Platelets and lipoproteins play a crucial role in atherogenesis, in part by their ability to modulate inflammation and oxidative stress. While oxidized low density lipoproteins (OxLDL) play a central role in the development of this disease, high density lipoproteins (HDL) represent an [...] Read more.
Platelets and lipoproteins play a crucial role in atherogenesis, in part by their ability to modulate inflammation and oxidative stress. While oxidized low density lipoproteins (OxLDL) play a central role in the development of this disease, high density lipoproteins (HDL) represent an atheroprotective factor of utmost importance. As platelet function is remarkably sensitive to the influence of plasma lipoproteins, it was the aim of this study to clarify if HDL are able to counteract the stimulating effects of OxLDL with special emphasis on aspects of platelet function that are relevant to inflammation. Therefore, HDL were tested for their ability to interfere with pro-thrombotic and pro-inflammatory aspects of platelet function. We are able to show that HDL significantly impaired OxLDL-induced platelet aggregation and adhesion. In gel-filtered platelets, HDL decreased both the formation of reactive oxygen species and CD40L expression. Furthermore, HDL strongly interfered with OxLDL-induced formation of platelet-neutrophil aggregates in whole blood, suggesting that platelets represent a relevant and sensitive target for HDL. The finding that HDL effectively competed with the binding of OxLDL to the platelet surface might contribute to their atheroprotective and antithrombotic properties. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Senescence Marker Protein-30 (SMP30) Deficiency Impairs Myocardium-Induced Dilation of Coronary Arterioles Associated with Reactive Oxygen Species
Int. J. Mol. Sci. 2013, 14(5), 9408-9423; doi:10.3390/ijms14059408
Received: 19 March 2013 / Revised: 15 April 2013 / Accepted: 16 April 2013 / Published: 29 April 2013
Cited by 7 | PDF Full-text (466 KB) | HTML Full-text | XML Full-text
Abstract
Senescence marker protein-30 (SMP30) decreases with aging. Mice with SMP30 deficiency, a model of aging, have a short lifespan with increased oxidant stress. To elucidate SMP30’s effect on coronary circulation derived from myocytes, we measured the changes in the diameter of isolated [...] Read more.
Senescence marker protein-30 (SMP30) decreases with aging. Mice with SMP30 deficiency, a model of aging, have a short lifespan with increased oxidant stress. To elucidate SMP30’s effect on coronary circulation derived from myocytes, we measured the changes in the diameter of isolated coronary arterioles in wild-type (WT) mice exposed to supernatant collected from isolated paced cardiac myocytes from SMP30 KO or WT mice. Pacing increased hydrogen peroxide in myocytes, and hydrogen peroxide was greater in SMP30 KO myocytes compared to WT myocytes. Antimycin enhanced and FCCP (oxidative phosphorylation uncoupler in mitochondria) decreased superoxide production in both groups. Addition of supernatant from stimulated myocytes, either SMP30 KO or WT, caused vasodilation. The degree of the vasodilation response to supernatant was smaller in SMP30 KO mice compared to WT mice. Administration of catalase to arterioles eliminated vasodilation in myocyte supernatant of WT mice and converted vasodilation to vasoconstriction in myocyte supernatant of SMP30 KO mice. This vasoconstriction was eliminated by olmesartan, an angiotensin II receptor antagonist. Thus, SMP30 deficiency combined with oxidant stress increases angiotensin and hydrogen peroxide release from cardiac myocytes. SMP30 plays an important role in the regulation of coronary vascular tone by myocardium. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Impact of High Salt Independent of Blood Pressure on PRMT/ADMA/DDAH Pathway in the Aorta of Dahl Salt-Sensitive Rats
Int. J. Mol. Sci. 2013, 14(4), 8062-8072; doi:10.3390/ijms14048062
Received: 20 January 2013 / Revised: 1 April 2013 / Accepted: 1 April 2013 / Published: 12 April 2013
Cited by 11 | PDF Full-text (373 KB) | HTML Full-text | XML Full-text
Abstract
Endothelial dysfunction participates in the development and progression of salt-sensitive hypertension. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). The objectives of this study were to investigate the impact of a high salt diet on the PRMT/ADMA/DDAH (protein [...] Read more.
Endothelial dysfunction participates in the development and progression of salt-sensitive hypertension. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). The objectives of this study were to investigate the impact of a high salt diet on the PRMT/ADMA/DDAH (protein arginine methyltransferases; dimethylarginine dimethylaminohydrolase) pathway in Dahl salt-sensitive (DS) rats and SS-13BN consomic (DR) rats, and to explore the mechanisms that regulate ADMA metabolism independent of blood pressure reduction. Plasma levels of nitric oxide (NO) in DS rats given a high salt diet and subjected to intragastric administration of hydralazine (SH + HYD group) were lower than those given a normal salt diet (SN group). There were significant decreases in expression and activity of dimethylarginine dimethylaminohydrolase (DDAH) and endothelial NO synthase (eNOS) in DS rats given a high diet (SH group) in comparison to the SN group. The activity of DDAH and expression of eNOS in the SH + HYD group decreased more significantly than SN group. The mRNA expression of DDAH-1 and DDAH-2 were lowest in the SH group. The results suggest that salt, independent of blood pressure, can affect the PRMT-1/ADMA/DDAH system to a certain degree and lead to endothelial dysfunction in Dahl salt-sensitive rats. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle Beneficial Effects of the RESMENA Dietary Pattern on Oxidative Stress in Patients Suffering from Metabolic Syndrome with Hyperglycemia Are Associated to Dietary TAC and Fruit Consumption
Int. J. Mol. Sci. 2013, 14(4), 6903-6919; doi:10.3390/ijms14046903
Received: 30 January 2013 / Revised: 8 March 2013 / Accepted: 19 March 2013 / Published: 27 March 2013
Cited by 17 | PDF Full-text (347 KB) | HTML Full-text | XML Full-text
Abstract
Hyperglycemia and oxidative stress are conditions directly related to the metabolic syndrome (MetS), whose prevalence is increasing worldwide. This study aimed to evaluate the effectiveness of a new weight-loss dietary pattern on improving the oxidative stress status on patients suffering MetS with [...] Read more.
Hyperglycemia and oxidative stress are conditions directly related to the metabolic syndrome (MetS), whose prevalence is increasing worldwide. This study aimed to evaluate the effectiveness of a new weight-loss dietary pattern on improving the oxidative stress status on patients suffering MetS with hyperglycemia. Seventy-nine volunteers were randomly assigned to two low-calorie diets (−30% Energy): the control diet based on the American Health Association criteria and the RESMENA diet based on a different macronutrient distribution (30% proteins, 30% lipids, 40% carbohydrates), which was characterized by an increase of the meal frequency (seven-times/day), low glycemic load, high antioxidant capacity (TAC) and high n-3 fatty acids content. Dietary records, anthropometrical measurements, biochemical parameters and oxidative stress biomarkers were analyzed before and after the six-month-long study. The RESMENA (Metabolic Syndrome Reduction in Navarra) diet specifically reduced the android fat mass and demonstrated more effectiveness on improving general oxidative stress through a greater decrease of oxidized LDL (oxLDL) values and protection against arylesterase depletion. Interestingly, oxLDL values were associated with dietary TAC and fruit consumption and with changes on body mass index (BMI), waist circumference, fat mass and triacilglyceride (TG) levels. In conclusion, the antioxidant properties of the RESMENA diet provide further benefits to those attributable to weight loss on patients suffering Mets with hyperglycemia. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessArticle The Protective Effects of α-Lipoic Acid on Kidneys in Type 2 Diabetic Goto-Kakisaki Rats via Reducing Oxidative Stress
Int. J. Mol. Sci. 2013, 14(4), 6746-6756; doi:10.3390/ijms14046746
Received: 9 December 2012 / Revised: 2 March 2013 / Accepted: 16 March 2013 / Published: 26 March 2013
Cited by 9 | PDF Full-text (1757 KB) | HTML Full-text | XML Full-text
Abstract
To evaluate the protective effects of α-lipoic acid on the kidneys of Goto-Kakisaki (GK) diabetic rats, ten GK diabetic rats were randomly divided into a diabetic control group and a lipoic acid-treated diabetic group with α-lipoic acid 35 mg·Kg−1 intraperitoneal injections. [...] Read more.
To evaluate the protective effects of α-lipoic acid on the kidneys of Goto-Kakisaki (GK) diabetic rats, ten GK diabetic rats were randomly divided into a diabetic control group and a lipoic acid-treated diabetic group with α-lipoic acid 35 mg·Kg−1 intraperitoneal injections. Four healthy Wistar rats served as normal controls. Malonaldehyde (MDA), ascorbic acid (vitamin C), vitamin E, glutathione (GSH) and superoxide dismutase (SOD) levels in renal homogenate, and urine protein excretion were measured. The expression of mRNA for NF-κB, NADPH oxidase subunits p22phox and p47phox in renal tissue was examined by realtime PCR. Pathological changes in renal tissue were evaluated by light and electron microscopy. There were significant increases in urine protein excretion, MDA levels and the expression of mRNA of NF-κB, p22phox and p47phox, and significant decreases in GSH, SOD, vitamin C and vitamin E levels in the diabetic control group compared with the normal control group. Pathological changes of renal tissue were more progressive in the diabetic control group than in the normal control group. All the parameters above were improved in the α-lipoic acid-treated diabetic group. Oxidative stress is increased in the kidney of type 2 diabetic GK rats. It is associated with the progression of diabetic nephropathy. α-lipoic acid can protect renal function in diabetic rats via its antioxidant activity. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)

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Open AccessReview Thyroid Hormones and Antioxidant Systems: Focus on Oxidative Stress in Cardiovascular and Pulmonary Diseases
Int. J. Mol. Sci. 2013, 14(12), 23893-23909; doi:10.3390/ijms141223893
Received: 18 September 2013 / Revised: 11 November 2013 / Accepted: 21 November 2013 / Published: 9 December 2013
Cited by 4 | PDF Full-text (410 KB) | HTML Full-text | XML Full-text
Abstract
In previous works we demonstrated an inverse correlation between plasma Coenzyme Q10 (CoQ10) and thyroid hormones; in fact, CoQ10 levels in hyperthyroid patients were found among the lowest detected in human diseases. On the contrary, CoQ10 is [...] Read more.
In previous works we demonstrated an inverse correlation between plasma Coenzyme Q10 (CoQ10) and thyroid hormones; in fact, CoQ10 levels in hyperthyroid patients were found among the lowest detected in human diseases. On the contrary, CoQ10 is elevated in hypothyroid subjects, also in subclinical conditions, suggesting the usefulness of this index in assessing metabolic status in thyroid disorders. A Low-T3 syndrome is a condition observed in several chronic diseases: it is considered an adaptation mechanism, where there is a reduction in pro-hormone T4 conversion. Low T3-Syndrome is not usually considered to be corrected with replacement therapy. We review the role of thyroid hormones in regulation of antioxidant systems, also presenting data on total antioxidant capacity and Coenzyme Q10. Published studies suggest that oxidative stress could be involved in the clinical course of different heart diseases; our data could support the rationale of replacement therapy in low-T3 conditions. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview Pathogenesis of Chronic Cardiorenal Syndrome: Is There a Role for Oxidative Stress?
Int. J. Mol. Sci. 2013, 14(11), 23011-23032; doi:10.3390/ijms141123011
Received: 3 August 2013 / Revised: 30 October 2013 / Accepted: 1 November 2013 / Published: 20 November 2013
Cited by 18 | PDF Full-text (535 KB) | HTML Full-text | XML Full-text
Abstract
Cardiorenal syndrome is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. Complex biochemical, hormonal and hemodynamic mechanisms underlie the development of cardiorenal syndrome. Both in vitro and experimental [...] Read more.
Cardiorenal syndrome is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. Complex biochemical, hormonal and hemodynamic mechanisms underlie the development of cardiorenal syndrome. Both in vitro and experimental studies have identified several dysregulated pathways in heart failure and in chronic kidney disease that lead to increased oxidative stress. A decrease in mitochondrial oxidative metabolism has been reported in cardiomyocytes during heart failure. This is balanced by a compensatory increase in glucose uptake and glycolysis with consequent decrease in myocardial ATP content. In the kidneys, both NADPH oxidase and mitochondrial metabolism are important sources of TGF-β1-induced cellular ROS. NOX-dependent oxidative activation of transcription factors such as NF-kB and c-jun leads to increased expression of renal target genes (phospholipaseA2, MCP-1 and CSF-1, COX-2), thus contributing to renal interstitial fibrosis and inflammation. In the present article, we postulate that, besides contributing to both cardiac and renal dysfunction, increased oxidative stress may also play a crucial role in cardiorenal syndrome development and progression. In particular, an imbalance between the renin-angiotensin-aldosterone system, the sympathetic nervous system, and inflammation may favour cardiorenal syndrome through an excessive oxidative stress production. This article also discusses novel therapeutic strategies for their potential use in the treatment of patients affected by cardiorenal syndrome. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview The NO/ONOO-Cycle as the Central Cause of Heart Failure
Int. J. Mol. Sci. 2013, 14(11), 22274-22330; doi:10.3390/ijms141122274
Received: 29 June 2013 / Revised: 23 October 2013 / Accepted: 24 October 2013 / Published: 13 November 2013
Cited by 12 | PDF Full-text (482 KB) | HTML Full-text | XML Full-text
Abstract
The NO/ONOO-cycle is a primarily local, biochemical vicious cycle mechanism, centered on elevated peroxynitrite and oxidative stress, but also involving 10 additional elements: NF-κB, inflammatory cytokines, iNOS, nitric oxide (NO), superoxide, mitochondrial dysfunction (lowered energy charge, ATP), NMDA activity, intracellular Ca2+ [...] Read more.
The NO/ONOO-cycle is a primarily local, biochemical vicious cycle mechanism, centered on elevated peroxynitrite and oxidative stress, but also involving 10 additional elements: NF-κB, inflammatory cytokines, iNOS, nitric oxide (NO), superoxide, mitochondrial dysfunction (lowered energy charge, ATP), NMDA activity, intracellular Ca2+, TRP receptors and tetrahydrobiopterin depletion. All 12 of these elements have causal roles in heart failure (HF) and each is linked through a total of 87 studies to specific correlates of HF. Two apparent causal factors of HF, RhoA and endothelin-1, each act as tissue-limited cycle elements. Nineteen stressors that initiate cases of HF, each act to raise multiple cycle elements, potentially initiating the cycle in this way. Different types of HF, left vs. right ventricular HF, with or without arrhythmia, etc., may differ from one another in the regions of the myocardium most impacted by the cycle. None of the elements of the cycle or the mechanisms linking them are original, but they collectively produce the robust nature of the NO/ONOO-cycle which creates a major challenge for treatment of HF or other proposed NO/ONOO-cycle diseases. Elevated peroxynitrite/NO ratio and consequent oxidative stress are essential to both HF and the NO/ONOO-cycle. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview Oxidative Stress in Diabetes: Implications for Vascular and Other Complications
Int. J. Mol. Sci. 2013, 14(11), 21525-21550; doi:10.3390/ijms141121525
Received: 22 August 2013 / Revised: 14 October 2013 / Accepted: 18 October 2013 / Published: 30 October 2013
Cited by 39 | PDF Full-text (524 KB) | HTML Full-text | XML Full-text
Abstract
In recent decades, oxidative stress has become a focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence shows that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, [...] Read more.
In recent decades, oxidative stress has become a focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence shows that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on these studies, an emerging concept is that oxidative stress is the “final common pathway” through which the risk factors for several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell–cell homeostasis; in particular, oxidative stress plays a key role in the pathogenesis of insulin resistance and β-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes and its vascular complications, the leading cause of death in diabetic patients. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
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Open AccessReview Protein Glutathionylation in Cardiovascular Diseases
Int. J. Mol. Sci. 2013, 14(10), 20845-20876; doi:10.3390/ijms141020845
Received: 29 August 2013 / Revised: 2 October 2013 / Accepted: 8 October 2013 / Published: 17 October 2013
Cited by 16 | PDF Full-text (586 KB) | HTML Full-text | XML Full-text
Abstract
The perturbation of thiol-disulfide homeostasis is an important consequence of many diseases, with redox signals implicated in several physio-pathological processes. A prevalent form of cysteine modification is the reversible formation of protein mixed disulfides with glutathione (S-glutathionylation). The abundance of [...] Read more.
The perturbation of thiol-disulfide homeostasis is an important consequence of many diseases, with redox signals implicated in several physio-pathological processes. A prevalent form of cysteine modification is the reversible formation of protein mixed disulfides with glutathione (S-glutathionylation). The abundance of glutathione in cells and the ready conversion of sulfenic acids to S-glutathione mixed disulfides supports the reversible protein S-glutathionylation as a common feature of redox signal transduction, able to regulate the activities of several redox sensitive proteins. In particular, protein S-glutathionylation is emerging as a critical signaling mechanism in cardiovascular diseases, because it regulates numerous physiological processes involved in cardiovascular homeostasis, including myocyte contraction, oxidative phosphorylation, protein synthesis, vasodilation, glycolytic metabolism and response to insulin. Thus, perturbations in protein glutathionylation status may contribute to the etiology of many cardiovascular diseases, such as myocardial infarction, cardiac hypertrophy and atherosclerosis. Various reports show the importance of oxidative cysteine modifications in modulating cardiovascular function. In this review, we illustrate tools and strategies to monitor protein S-glutathionylation and describe the proteins so far identified as glutathionylated in myocardial contraction, hypertrophy and inflammation. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview The Epidermal Growth Factor Receptor and Its Ligands in Cardiovascular Disease
Int. J. Mol. Sci. 2013, 14(10), 20597-20613; doi:10.3390/ijms141020597
Received: 24 July 2013 / Revised: 20 September 2013 / Accepted: 8 October 2013 / Published: 15 October 2013
Cited by 20 | PDF Full-text (635 KB) | HTML Full-text | XML Full-text
Abstract
The epidermal growth factor receptor (EGFR) family and its ligands serve as a switchboard for the regulation of multiple cellular processes. While it is clear that EGFR activity is essential for normal cardiac development, its function in the vasculature and its role [...] Read more.
The epidermal growth factor receptor (EGFR) family and its ligands serve as a switchboard for the regulation of multiple cellular processes. While it is clear that EGFR activity is essential for normal cardiac development, its function in the vasculature and its role in cardiovascular disease are only beginning to be elucidated. In the blood vessel, endothelial cells and smooth muscle cells are both a source and a target of EGF-like ligands. Activation of EGFR has been implicated in blood pressure regulation, endothelial dysfunction, neointimal hyperplasia, atherogenesis, and cardiac remodeling. Furthermore, increased circulating EGF-like ligands may mediate accelerated vascular disease associated with chronic inflammation. Although EGFR inhibitors are currently being used clinically for the treatment of cancer, additional studies are necessary to determine whether abrogation of EGFR signaling is a potential strategy for the treatment of cardiovascular disease. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
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Open AccessReview Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond
Int. J. Mol. Sci. 2013, 14(10), 19891-19910; doi:10.3390/ijms141019891
Received: 8 August 2013 / Revised: 5 September 2013 / Accepted: 5 September 2013 / Published: 1 October 2013
Cited by 51 | PDF Full-text (457 KB) | HTML Full-text | XML Full-text
Abstract
Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS) and consequent downstream signal [...] Read more.
Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS) and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview Renal Dopamine Receptors, Oxidative Stress, and Hypertension
Int. J. Mol. Sci. 2013, 14(9), 17553-17572; doi:10.3390/ijms140917553
Received: 1 July 2013 / Revised: 9 August 2013 / Accepted: 12 August 2013 / Published: 27 August 2013
Cited by 17 | PDF Full-text (488 KB) | HTML Full-text | XML Full-text
Abstract
Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) [...] Read more.
Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview Oxidative Stress and MicroRNAs in Vascular Diseases
Int. J. Mol. Sci. 2013, 14(9), 17319-17346; doi:10.3390/ijms140917319
Received: 27 June 2013 / Revised: 25 July 2013 / Accepted: 26 July 2013 / Published: 22 August 2013
Cited by 49 | PDF Full-text (731 KB) | HTML Full-text | XML Full-text
Abstract
Oxidative stress has been demonstrated to play a causal role in different vascular diseases, such as hypertension, diabetic vasculopathy, hypercholesterolemia and atherosclerosis. Indeed, increased reactive oxygen species (ROS) production is known to impair endothelial and vascular smooth muscle cell functions, contributing to [...] Read more.
Oxidative stress has been demonstrated to play a causal role in different vascular diseases, such as hypertension, diabetic vasculopathy, hypercholesterolemia and atherosclerosis. Indeed, increased reactive oxygen species (ROS) production is known to impair endothelial and vascular smooth muscle cell functions, contributing to the development of cardiovascular diseases. MicroRNAs (miRNAs) are non-coding RNA molecules that modulate the stability and/or the translational efficiency of target messenger RNAs. They have been shown to be modulated in most biological processes, including in cellular responses to redox imbalance. In particular, miR-200 family members play a crucial role in oxidative-stress dependent endothelial dysfunction, as well as in cardiovascular complications of diabetes and obesity. In addition, different miRNAs, such as miR-210, have been demonstrated to play a key role in mitochondrial metabolism, therefore modulating ROS production and sensitivity. In this review, we will discuss miRNAs modulated by ROS or involved in ROS production, and implicated in vascular diseases in which redox imbalance has a pathogenetic role. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview The Role of Antioxidation and Immunomodulation in Postnatal Multipotent Stem Cell-Mediated Cardiac Repair
Int. J. Mol. Sci. 2013, 14(8), 16258-16279; doi:10.3390/ijms140816258
Received: 30 May 2013 / Revised: 23 July 2013 / Accepted: 30 July 2013 / Published: 6 August 2013
Cited by 7 | PDF Full-text (277 KB) | HTML Full-text | XML Full-text
Abstract
Oxidative stress and inflammation play major roles in the pathogenesis of coronary heart disease including myocardial infarction (MI). The pathological progression following MI is very complex and involves a number of cell populations including cells localized within the heart, as well as [...] Read more.
Oxidative stress and inflammation play major roles in the pathogenesis of coronary heart disease including myocardial infarction (MI). The pathological progression following MI is very complex and involves a number of cell populations including cells localized within the heart, as well as cells recruited from the circulation and other tissues that participate in inflammatory and reparative processes. These cells, with their secretory factors, have pleiotropic effects that depend on the stage of inflammation and regeneration. Excessive inflammation leads to enlargement of the infarction site, pathological remodeling and eventually, heart dysfunction. Stem cell therapy represents a unique and innovative approach to ameliorate oxidative stress and inflammation caused by ischemic heart disease. Consequently, it is crucial to understand the crosstalk between stem cells and other cells involved in post-MI cardiac tissue repair, especially immune cells, in order to harness the beneficial effects of the immune response following MI and further improve stem cell-mediated cardiac regeneration. This paper reviews the recent findings on the role of antioxidation and immunomodulation in postnatal multipotent stem cell-mediated cardiac repair following ischemic heart disease, particularly acute MI and focuses specifically on mesenchymal, muscle and blood-vessel-derived stem cells due to their antioxidant and immunomodulatory properties. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview S-Glutathionylation in Monocyte and Macrophage (Dys)Function
Int. J. Mol. Sci. 2013, 14(8), 15212-15232; doi:10.3390/ijms140815212
Received: 3 June 2013 / Revised: 15 June 2013 / Accepted: 18 June 2013 / Published: 24 July 2013
Cited by 9 | PDF Full-text (240 KB) | HTML Full-text | XML Full-text
Abstract
Atherosclerosis is a chronic inflammatory disease involving the accumulation of monocytes and macrophages in the vascular wall. Monocytes and macrophages play a central role in the initiation and progression of atherosclerotic lesion development. Oxidative stress, which occurs when reactive oxygen species (ROS) [...] Read more.
Atherosclerosis is a chronic inflammatory disease involving the accumulation of monocytes and macrophages in the vascular wall. Monocytes and macrophages play a central role in the initiation and progression of atherosclerotic lesion development. Oxidative stress, which occurs when reactive oxygen species (ROS) overwhelm cellular antioxidant systems, contributes to the pathophysiology of many chronic inflammatory diseases, including atherosclerosis. Major targets of ROS are reactive thiols on cysteine residues in proteins, which when oxidized can alter cellular processes, including signaling pathways, metabolic pathways, transcription, and translation. Protein-S-glutathionylation is the process of mixed disulfide formation between glutathione (GSH) and protein thiols. Until recently, protein-S-glutathionylation was associated with increased cellular oxidative stress, but S-glutathionylation of key protein targets has now emerged as a physiologically important redox signaling mechanism, which when dysregulated contributes to a variety of disease processes. In this review, we will explore the role of thiol oxidative stress and protein-S-glutathionylation in monocyte and macrophage dysfunction as a mechanistic link between oxidative stress associated with metabolic disorders and chronic inflammatory diseases, including atherosclerosis. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview Chlamydia pneumoniae Infection in Atherosclerotic Lesion Development through Oxidative Stress: A Brief Overview
Int. J. Mol. Sci. 2013, 14(7), 15105-15120; doi:10.3390/ijms140715105
Received: 31 May 2013 / Revised: 4 July 2013 / Accepted: 10 July 2013 / Published: 19 July 2013
Cited by 13 | PDF Full-text (577 KB) | HTML Full-text | XML Full-text
Abstract
Chlamydia pneumoniae, an obligate intracellular pathogen, is known as a leading cause of respiratory tract infections and, in the last two decades, has been widely associated with atherosclerosis by seroepidemiological studies, and direct detection of the microorganism within atheroma. C. pneumoniae [...] Read more.
Chlamydia pneumoniae, an obligate intracellular pathogen, is known as a leading cause of respiratory tract infections and, in the last two decades, has been widely associated with atherosclerosis by seroepidemiological studies, and direct detection of the microorganism within atheroma. C. pneumoniae is presumed to play a role in atherosclerosis for its ability to disseminate via peripheral blood mononuclear cells, to replicate and persist within vascular cells, and for its pro-inflammatory and angiogenic effects. Once inside the vascular tissue, C. pneumoniae infection has been shown to induce the production of reactive oxygen species in all the cells involved in atherosclerotic process such as macrophages, platelets, endothelial cells, and vascular smooth muscle cells, leading to oxidative stress. The aim of this review is to summarize the data linking C. pneumoniae-induced oxidative stress to atherosclerotic lesion development. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview The Efficacy of Edaravone (Radicut), a Free Radical Scavenger, for Cardiovascular Disease
Int. J. Mol. Sci. 2013, 14(7), 13909-13930; doi:10.3390/ijms140713909
Received: 23 May 2013 / Revised: 19 June 2013 / Accepted: 21 June 2013 / Published: 4 July 2013
Cited by 17 | PDF Full-text (261 KB) | HTML Full-text | XML Full-text
Abstract
Edaravone was originally developed as a potent free radical scavenger, and has been widely used to treat acute ischemic stroke in Japan since 2001. Free radicals play an important role in the pathogenesis of a variety of diseases, such as cardiovascular diseases [...] Read more.
Edaravone was originally developed as a potent free radical scavenger, and has been widely used to treat acute ischemic stroke in Japan since 2001. Free radicals play an important role in the pathogenesis of a variety of diseases, such as cardiovascular diseases and stroke. Therefore, free radicals may be targets for therapeutic intervention in these diseases. Edaravone shows protective effects on ischemic insults and inflammation in the heart, vessel, and brain in experimental studies. As well as scavenging free radicals, edaravone has anti-apoptotic, anti-necrotic, and anti-cytokine effects in cardiovascular diseases and stroke. Edaravone has preventive effects on myocardial injury following ischemia and reperfusion in patients with acute myocardial infarction. Edaravone may represent a new therapeutic intervention for endothelial dysfunction in the setting of atherosclerosis, heart failure, diabetes, or hypertension, because these diseases result from oxidative stress and/or cytokine-induced apoptosis. This review evaluates the potential of edaravone for treatment of cardiovascular disease, and covers clinical and experimental studies conducted between 1984 and 2013. We propose that edaravone, which scavenges free radicals, may offer a novel option for treatment of cardiovascular diseases. However, additional clinical studies are necessary to verify the efficacy of edaravone. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
Open AccessReview Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins
Int. J. Mol. Sci. 2013, 14(6), 12696-12713; doi:10.3390/ijms140612696
Received: 10 April 2013 / Revised: 11 May 2013 / Accepted: 5 June 2013 / Published: 17 June 2013
Cited by 23 | PDF Full-text (233 KB) | HTML Full-text | XML Full-text
Abstract
The development of atherosclerosis is a multi-step process, at least in part controlled by the vascular endothelium function. Observations in humans and experimental models of atherosclerosis have identified monocyte recruitment as an early event in atherogenesis. Chronic inflammation is associated with ageing [...] Read more.
The development of atherosclerosis is a multi-step process, at least in part controlled by the vascular endothelium function. Observations in humans and experimental models of atherosclerosis have identified monocyte recruitment as an early event in atherogenesis. Chronic inflammation is associated with ageing and its related diseases (e.g., atherosclerosis and chronic obstructive pulmonary disease). Recently it has been discovered that Sirtuins (NAD+-dependent deacetylases) represent a pivotal regulator of longevity and health. They appear to have a prominent role in vascular biology and regulate aspects of age-dependent atherosclerosis. Many studies demonstrate that SIRT1 exhibits anti-inflammatory properties in vitro (e.g., fatty acid-induced inflammation), in vivo (e.g., atherosclerosis, sustainment of normal immune function in knock-out mice) and in clinical studies (e.g., patients with chronic obstructive pulmonary disease). Because of a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke and in lungs of patients with chronic obstructive pulmonary disease (COPD), activation of SIRT1 may be a potential target for chronic obstructive pulmonary disease therapy. We review the inflammatory mechanisms involved in COPD-CVD coexistence and the potential role of SIRT1 in the regulation of these systems. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)
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