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Oxidative Stress in Hypertension: Mechanisms and Potential Pharmacological Targets

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

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 23565

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Dr. Anna Dikalova

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Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Interests: oxidative stress; endothelial dysfunction; vascular dysfunction; systemic hypertension; pulmonary hypertension; mitochondrial dysfunction
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Special Issue Information

Dear colleagues,

Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure, which cause one-third of deaths worldwide. Hypertension is a multifactorial disorder involving perturbations of the vasculature, kidney, and immune and central nervous systems. Despite treatment with multiple drugs, 37% of hypertensive patients remain hypertensive, likely due to mechanisms contributing to blood pressure elevation that are not affected by current treatments. Unraveling the underlying causes of vascular dysfunction is critical to improving disease burden. Metabolic disorders and oxidative stress contribute to the pathogenesis of vascular dysfunction and hypertension which are associated with mitochondrial dysfunction and altered cell redox signaling. Targeting specific sources of oxidative stress such as NADPH oxidases or mitochondrial metabolic functions can improve vascular function, reduce hypertension, and reduce morbidity and mortality associated with these pathological conditions.

In this Special Issue, we will discuss the novel mechanisms of oxidative stress, its role in metabolic dysregulation and inflammation, and describe the therapeutic potential of targeting specific oxidative stress and metabolic pathways to improve vascular function and reduce hypertension.

Prof. Anna Dikalova
Guest Editor

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Keywords

Essential hypertension
Pulmonary hypertension
Endothelial dysfunction
Vascular hypertrophy
Inflammation
Oxidative stress
Mitochondria
Metabolic conditions
Superoxide radical
Superoxide dismutase
Isolevuglandins
NADPH oxidase

Published Papers (5 papers)

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Research

18 pages, 3710 KiB

Open AccessArticle

Aldosterone Induces DNA Damage and Activation of Nrf2 Mainly in Tubuli of Mouse Kidneys

by Ronja Balhorn, Christina Hartmann and Nicole Schupp

Int. J. Mol. Sci. 2020, 21(13), 4679; https://doi.org/10.3390/ijms21134679 - 30 Jun 2020

Cited by 4 | Viewed by 2600

Abstract

Hypertensive patients have an increased risk of developing chronic kidney disease (CKD). Many of these patients have increased levels of the blood pressure regulating mineralocorticoid aldosterone. As a protection against aldosterone-induced damage, kidney cells can upregulate key regulators of the antioxidant defense, such as nuclear factor-erythroid-2-related factor 2 (Nrf2). In the present study aldosterone-induced kidney damage and Nrf2 activation in kidney cells of mice treated with three different concentrations of aldosterone for 4 weeks was localized. Increased albumin and neutrophil gelatinase-associated lipocalin (NGAL) in urine revealed an impaired kidney function of the aldosterone-infused mice. Localization of aldosterone-induced oxidative damage (in the form of DNA lesions) in specific kidney cells showed an increase in proximal tubuli and to an even greater extend in distal tubuli. Phosphorylated Nrf2 was increased in distal tubule cells after aldosterone-infusion. Nrf2 activation in proximal tubuli or in glomeruli after aldosterone-treatment could not be observed. Nrf2 target genes and proteins analyzed, paradoxically, showed a downregulation in the whole kidney. Aldosterone-treated mice exhibited an increased kidney injury and DNA damage in distal and proximal tubuli. Nrf2 seemed only to be specifically activated in distal tubule cells, where we also detected the highest amount of oxidative damage. Full article

(This article belongs to the Special Issue Oxidative Stress in Hypertension: Mechanisms and Potential Pharmacological Targets)

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11 pages, 956 KiB

Open AccessArticle

NADPH Oxidase Overactivity Underlies Telomere Shortening in Human Atherosclerosis

by Álvaro Pejenaute, Adriana Cortés, Javier Marqués, Laura Montero, Óscar Beloqui, Ana Fortuño, Amelia Martí, Josune Orbe and Guillermo Zalba

Int. J. Mol. Sci. 2020, 21(4), 1434; https://doi.org/10.3390/ijms21041434 - 20 Feb 2020

Cited by 19 | Viewed by 2775

Abstract

Telomere shortening and oxidative stress are involved in the pathogenesis of atherosclerosis. Different studies have shown that phagocytic NADPH oxidase is associated with this disease. This study aimed to investigate the association between phagocytic NADPH oxidase and telomere shortening in human atherosclerosis. To assess this potential association, telomere length and phagocytic NADPH oxidase activity were determined by PCR and chemiluminescence, respectively, in a population of asymptomatic subjects free of overt clinical atherosclerosis. We also measured serum 8-hydroxy-2-deoxyguanosine (8-OHdG) levels (an index of oxidative stress) and carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis. After adjusting them for age and sex, telomere length inversely correlated (p < 0.05) with NADPH oxidase-mediated superoxide production, with 8-OHdG values, and with carotid IMT. Interestingly, the asymptomatic subjects with plaques have a lower telomere length (p < 0.05), and higher values of plasma 8-OHdG and superoxide production (p < 0.05). These data were confirmed in a second population in which patients with coronary artery disease showed lower telomere length and higher 8-OHdG and superoxide production than the asymptomatic subjects. In both studies, NADPH oxidase-dependent superoxide production in phagocytic cells was only due to the specific expression of the Nox2 isoform. In conclusion, these findings suggest that phagocytic NADPH oxidase may be involved in oxidative stress-mediated telomere shortening, and that this axis may be critically involved in human atherosclerosis. Full article

(This article belongs to the Special Issue Oxidative Stress in Hypertension: Mechanisms and Potential Pharmacological Targets)

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24 pages, 5309 KiB

Open AccessArticle

Chronic Cannabidiol Administration Fails to Diminish Blood Pressure in Rats with Primary and Secondary Hypertension Despite Its Effects on Cardiac and Plasma Endocannabinoid System, Oxidative Stress and Lipid Metabolism

by Patryk Remiszewski, Iwona Jarocka-Karpowicz, Michał Biernacki, Anna Jastrząb, Eberhard Schlicker, Marek Toczek, Ewa Harasim-Symbor, Anna Pędzińska-Betiuk and Barbara Malinowska

Int. J. Mol. Sci. 2020, 21(4), 1295; https://doi.org/10.3390/ijms21041295 - 14 Feb 2020

Cited by 37 | Viewed by 5053

Abstract

We investigated the influence of cannabidiol (CBD) on blood pressure (BP) and heart rate (HR) in spontaneously (SHR) and deoxycorticosterone (DOCA-salt) hypertensive rats. Hypertension was connected with increases in cardiac and plasma markers of lipid peroxidation in both models, whereas cardiac endocannabinoid levels decreased in SHR and increased in DOCA-salt. CBD (10 mg/kg once a day for 2 weeks) did not modify BP and HR in hypertension but counteracted pro-oxidant effects. Moreover, it decreased cardiac or plasma levels of anandamide, 2-arachidonoylglycerol and oleoyl ethanolamide in DOCA-salt and inhibited the activity of fatty acid amide hydrolase (FAAH) in both models. In the respective normotensive control rats, CBD increased lipid peroxidation, free fatty acid levels and FAAH activity. In conclusion, chronic CBD administration does not possess antihypertensive activity in a model of primary and secondary (DOCA-salt) hypertension, despite its antioxidant effect. The latter may be direct rather than based on the endocannabinoid system. The unexpected CBD-related increase in lipid peroxidation in normotensive controls may lead to untoward effects; thus, caution should be kept if CBD is used therapeutically. Full article

(This article belongs to the Special Issue Oxidative Stress in Hypertension: Mechanisms and Potential Pharmacological Targets)

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11 pages, 3024 KiB

Open AccessArticle

Conditioned Medium from Human Adipose-Derived Mesenchymal Stem Cell Culture Prevents UVB-Induced Skin Aging in Human Keratinocytes and Dermal Fibroblasts

by Lu Li, Hien T.T. Ngo, Eunson Hwang, Xuan Wei, Ying Liu, Jia Liu and Tae-Hoo Yi

Int. J. Mol. Sci. 2020, 21(1), 49; https://doi.org/10.3390/ijms21010049 - 19 Dec 2019

Cited by 72 | Viewed by 9543

Abstract

Human adipose-derived mesenchymal stem cells-conditioned medium (ADSC-CM) contains cytokines and growth factors that can facilitate the regeneration and repair of various tissues and organs. In the present study, the protective activity of ADSC-CM treatment was investigated in UVB-irradiated human keratinocyte cell line HaCaTs and normal human dermal fibroblasts (NHDFs). It was found that ADSC-CM can modulate the expression of the signaling molecules in the early UVB responsive signaling pathways, including mitogen activated protein kinases (MAPKs), activator protein 1 (AP-1), and nuclear factor kappa B (NF-κB). In addition, ADSC-CM treatment could upregulate antioxidant response element (ARE) such as phase II gene heme oxygenase-1 (HO-1) and increase the expression of collagen synthesis enhancer gene transforming growth factor-β (TGF-β). The expression of matrix metalloproteinase-1 (MMP-1) and procollagen type I synthesis inhibitors such as interleukin-6 (IL-6) was also found to be suppressed upon ADSC-CM treatment. Taken together, our study illustrates the anti-photoaging activities of ADSC-CM in cell-based models. Full article

(This article belongs to the Special Issue Oxidative Stress in Hypertension: Mechanisms and Potential Pharmacological Targets)

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13 pages, 2463 KiB

Open AccessArticle

Protection of Male Rat Offspring against Hypertension Programmed by Prenatal Dexamethasone Administration and Postnatal High-Fat Diet with the Nrf2 Activator Dimethyl Fumarate during Pregnancy

by Chien-Ning Hsu, Yu-Ju Lin, Hong-Ren Yu, I-Chun Lin, Jiunn-Ming Sheen, Li-Tung Huang and You-Lin Tain

Int. J. Mol. Sci. 2019, 20(16), 3957; https://doi.org/10.3390/ijms20163957 - 14 Aug 2019

Cited by 31 | Viewed by 3150

Abstract

Hypertension can originate from early-life exposure to oxidative stress. As reported, dimethyl fumarate (DMF) activates nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and protects against oxidative stress damage. We examined whether maternal DMF therapy protects adult offspring against hypertension programmed by prenatal dexamethasone (DEX) and postnatal high-fat (HF) diet exposure. We examined male Sprague Dawley rat offspring at 4 months of age from five groups (n = 11–13/group): control, DEX (0.1mg/kg i.p. from gestational day 16 to 22), HF (D12331 diet from weaning to 16 weeks of age), DEX+HF, and DEX+HF+DMF (50mg/kg/day via gastric gavage for 3 weeks during pregnancy). Maternal DMF therapy prevented male offspring against hypertension programmed by combined DEX and HF exposures. The protective effects of maternal DMF include reduced oxidative stress, decreased plasma asymmetric dimethylarginine (ADMA) levels, downregulated the renin-angiotensin system (i.e. Ren, Agt, Ace, and Agtr1a), increased renal protein levels of certain nutrient-sensing signals, and promoted autophagy. In conclusion, maternal Nrf2 activation by DMF protects male adult offspring against hypertension programmed by combined DEX and HF exposures. Our results cast a new light on the therapeutic potential of targeting Nrf2 signaling pathway as reprogramming strategies to prevent programmed hypertension in children exposed to antenatal corticosteroids and postnatally excessive consumption of fat. Full article

(This article belongs to the Special Issue Oxidative Stress in Hypertension: Mechanisms and Potential Pharmacological Targets)

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Oxidative Stress in Hypertension: Mechanisms and Potential Pharmacological Targets

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