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Special Issue "Mechanisms of Inflammation in Degenerative Cardiovascular Conditions"

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

Deadline for manuscript submissions: closed (31 March 2019)

Special Issue Editors

Guest Editor
Prof. Dr. Guido Iaccarino

Università di Napoli Federico II, Dipartimento di Scienze Biomediche Avanzate, (Napoli), Italy
Website 1 | Website 2 | E-Mail
Interests: beta adrenergic receotor; signaling; GRKs; mitochondia; hypertension; cardiac hypertrophy; heart failure
Guest Editor
Dr. Daniela Daniela Sorriento

Università degli Studi di Napoli Federico II, Dipartimento di Scienze Biomediche Avanzate, Naples, Italy
Website | E-Mail

Special Issue Information

Dear Colleagues,

The burden of cardiovascular disease in Western societies keeps growing, and continues to be the main causes of death. Research in the field for the investigation of new molecular mechanisms triggers the development of modern therapeutics. In the last few decades, multiple lines of evidence have suggested that inflammation is a key player in the development of cardiovascular diseases, accompanying this condition along its continuum. Indeed, inflamation coexists with many of the cardiovascular risk factors (smoke, obesity, dyslipidemia, hypertension, aging). Additionally, chronic inflammatory diseases, such as rheumatoid arthritis, also present increased cartdiovascular risk. The very mechanisms of target organ damage includes inflammatory responses and inflamation cell infiltration. Moreover, targeting mechanisms of inflamation, such as pro-inflammatory cytokines (IL1β, TNFα), effectively affect the clinical outcomes of heart diseases, supporting the entangled role of inflamation in cardiovascular events. In this context, the transcription factor NF-kB is emerging as potential therapeutic target since it regulates the expression of inflammatory cytokines but it is also associated with the development of heart diseases. In this field drugs-dependent cardiotoxicity is also included since Doxorubicin increases proinflammatory cytokines levels (TNF-α and IL-6) with a concomitant reduction of anti-inflammatory ones (IL-10), that could be responsible for the later onset of heart remodeling that leads to doxorubicin-dependent cardiomyopathy.

This Special Issue is a call for publication for all those reserchers that have paved the area with their findings, but also an opportunity for cross fertilization of the scenario by engaging basic scientists and clinicians to confront their ideas and their views, for the progression of the field. Authors are welcome to contribute original research articles, current review articles and commentaries.

Prof. Dr. Guido Iaccarino
Dr. Daniela Daniela Sorriento
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Inflammation
  • cytokines
  • NFkappaB
  • cardiovascular diseases
  • Target organ damage
  • Cardiovascular risk
  • drug-induced cardiotoxicity
  • Free Oxygen Radicals
  • novel anti-inflammatory therapies
  • Signal transduction

Published Papers (14 papers)

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Research

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Open AccessArticle
CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy
Int. J. Mol. Sci. 2019, 20(9), 2267; https://doi.org/10.3390/ijms20092267
Received: 3 April 2019 / Revised: 3 May 2019 / Accepted: 6 May 2019 / Published: 8 May 2019
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Abstract
Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates β-adrenergic receptor (β-AR) signaling and ultimately limits β-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment [...] Read more.
Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates β-adrenergic receptor (β-AR) signaling and ultimately limits β-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to β-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates β-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessArticle
Inflammatory, Serological and Vascular Determinants of Cardiovascular Disease in Systemic Lupus Erythematosus Patients
Int. J. Mol. Sci. 2019, 20(9), 2154; https://doi.org/10.3390/ijms20092154
Received: 1 March 2019 / Revised: 16 April 2019 / Accepted: 24 April 2019 / Published: 30 April 2019
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Abstract
Background and aim: Systemic lupus erythematosus (SLE) is associated with increased risk of cardiovascular disease (CVD). Among many mechanisms, accelerated atherosclerosis, endothelial dysfunction, and hypercoagulability play a main role. Here, we investigate whether inflammatory, serological and clinical markers of SLE determine and correlate [...] Read more.
Background and aim: Systemic lupus erythematosus (SLE) is associated with increased risk of cardiovascular disease (CVD). Among many mechanisms, accelerated atherosclerosis, endothelial dysfunction, and hypercoagulability play a main role. Here, we investigate whether inflammatory, serological and clinical markers of SLE determine and correlate with arterial stiffness in SLE patients. Materials and methods: Routine blood samples, inflammatory mediators, specific antibodies, and 24 h proteinuria were measured in 43 SLE patients and 43 age and sex-matched controls using routine laboratory assays. We also assessed arterial stiffness by measuring radial artery applanation tonometry-derived augmentation index (AI), normalized AI ([email protected]), aortic pulse pressure, central systolic, diastolic and peripheral blood pressure. Results: SLE patients showed a significantly greater arterial stiffness vs. controls, as demonstrated by the significantly higher [email protected] and aortic pulse pressure. Interestingly, regression analysis showed that age, systolic pulse pressure, inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), daily dose of glucocorticoids, and cumulative organ damage positively correlated with arterial stiffness. Conclusions: SLE patients show increased arterial stiffness which correlates with markers of inflammation, that is involved in early alterations in arterial walls. Applanation tonometry can be used to screen SLE patients for subclinical vascular damage to implement prevention strategies for CVD. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessArticle
Superantigenic Activation of Human Cardiac Mast Cells
Int. J. Mol. Sci. 2019, 20(8), 1828; https://doi.org/10.3390/ijms20081828
Received: 13 March 2019 / Revised: 9 April 2019 / Accepted: 10 April 2019 / Published: 12 April 2019
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Abstract
B cell superantigens, also called immunoglobulin superantigens, bind to the variable regions of either the heavy or light chain of immunoglobulins mirroring the lymphocyte-activating properties of classical T cell superantigens. Protein A of Staphylococcus aureus, protein L of Peptostreptococcus magnus, and [...] Read more.
B cell superantigens, also called immunoglobulin superantigens, bind to the variable regions of either the heavy or light chain of immunoglobulins mirroring the lymphocyte-activating properties of classical T cell superantigens. Protein A of Staphylococcus aureus, protein L of Peptostreptococcus magnus, and gp120 of HIV are typical immunoglobulin superantigens. Mast cells are immune cells expressing the high-affinity receptor for IgE (FcεRI) and are strategically located in the human heart, where they play a role in several cardiometabolic diseases. Here, we investigated whether immunoglobulin superantigens induced the activation of human heart mast cells (HHMCs). Protein A induced the de novo synthesis of cysteinyl leukotriene C4 (LTC4) from HHMCs through the interaction with IgE VH3+ bound to FcεRI. Protein L stimulated the production of prostaglandin D2 (PGD2) from HHMCs through the interaction with κ light chains of IgE. HIV glycoprotein gp120 induced the release of preformed (histamine) and de novo synthesized mediators, such as cysteinyl leukotriene C4 (LTC4), angiogenic (VEGF-A), and lymphangiogenic (VEGF-C) factors by interacting with the VH3 region of IgE. Collectively, our data indicate that bacterial and viral immunoglobulin superantigens can interact with different regions of IgE bound to FcεRI to induce the release of proinflammatory, angiogenic, and lymphangiogenic factors from human cardiac mast cells. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessArticle
Antidiabetic and Cardioprotective Effects of Pharmacological Inhibition of GRK2 in db/db Mice
Int. J. Mol. Sci. 2019, 20(6), 1492; https://doi.org/10.3390/ijms20061492
Received: 27 February 2019 / Revised: 17 March 2019 / Accepted: 20 March 2019 / Published: 25 March 2019
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Abstract
Despite the availability of several therapies for the management of blood glucose in diabetic patients, most of the treatments do not show benefits on diabetic cardiomyopathy, while others even favor the progression of the disease. New pharmacological targets are needed that might help [...] Read more.
Despite the availability of several therapies for the management of blood glucose in diabetic patients, most of the treatments do not show benefits on diabetic cardiomyopathy, while others even favor the progression of the disease. New pharmacological targets are needed that might help the management of diabetes and its cardiovascular complications at the same time. GRK2 appears a promising target, given its established role in insulin resistance and in systolic heart failure. Using a custom peptide inhibitor of GRK2, we assessed in vitro in L6 myoblasts the effects of GRK2 inhibition on glucose extraction and insulin signaling. Afterwards, we treated diabetic male mice (db/db) for 2 weeks. Glucose tolerance (IGTT) and insulin sensitivity (ITT) were ameliorated, as was skeletal muscle glucose uptake and insulin signaling. In the heart, at the same time, the GRK2 inhibitor ameliorated inflammatory and cytokine responses, reduced oxidative stress, and corrected patterns of fetal gene expression, typical of diabetic cardiomyopathy. GRK2 inhibition represents a promising therapeutic target for diabetes and its cardiovascular complications. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessArticle
Deletion of Osteopontin Enhances β2-Adrenergic Receptor-Dependent Anti-Fibrotic Signaling in Cardiomyocytes
Int. J. Mol. Sci. 2019, 20(6), 1396; https://doi.org/10.3390/ijms20061396
Received: 28 February 2019 / Revised: 13 March 2019 / Accepted: 15 March 2019 / Published: 20 March 2019
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Abstract
Cardiac β2-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. The β2AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates the generation of cyclic 3′,5′-adenosine monophosphate (cAMP). cAMP has [...] Read more.
Cardiac β2-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. The β2AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates the generation of cyclic 3′,5′-adenosine monophosphate (cAMP). cAMP has two effectors: protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac). Epac1 has been shown to inhibit cardiac fibroblast activation and fibrosis. Osteopontin (OPN) is a ubiquitous pro-inflammatory cytokine, which also mediates fibrosis in several tissues, including the heart. OPN underlies several cardiovascular pathologies, including atherosclerosis and cardiac adverse remodeling. We found that the cardiotoxic hormone aldosterone transcriptionally upregulates OPN in H9c2 rat cardiac myoblasts—an effect prevented by endogenous β2AR activation. Additionally, CRISPR-mediated OPN deletion enhanced cAMP generation in response to both β1AR and β2AR activation in H9c2 cardiomyocytes, leading to the upregulation of Epac1 protein levels. These effects rendered β2AR stimulation capable of completely abrogating transforming growth factor (TGF)-β-dependent fibrosis in OPN-lacking H9c2 cardiomyocytes. Finally, OPN interacted constitutively with Gαs subunits in H9c2 cardiac cells. Thus, we uncovered a direct inhibitory role of OPN in cardiac β2AR anti-fibrotic signaling via cAMP/Epac1. OPN blockade could be of value in the treatment and/or prevention of cardiac fibrosis. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessCommunication
T-Cell Accumulation in the Hypertensive Brain: A Role for Sphingosine-1-Phosphate-Mediated Chemotaxis
Int. J. Mol. Sci. 2019, 20(3), 537; https://doi.org/10.3390/ijms20030537
Received: 19 December 2018 / Revised: 25 January 2019 / Accepted: 25 January 2019 / Published: 28 January 2019
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Abstract
Hypertension is considered the major modifiable risk factor for the development of cognitive impairment. Because increased blood pressure is often accompanied by an activation of the immune system, the concept of neuro-inflammation gained increasing attention in the field of hypertension-associated neurodegeneration. Particularly, hypertension-associated [...] Read more.
Hypertension is considered the major modifiable risk factor for the development of cognitive impairment. Because increased blood pressure is often accompanied by an activation of the immune system, the concept of neuro-inflammation gained increasing attention in the field of hypertension-associated neurodegeneration. Particularly, hypertension-associated elevated circulating T-lymphocyte populations and target organ damage spurred the interest to understanding mechanisms leading to inflammation-associated brain damage during hypertension. The present study describes sphingosine-1-phosphate (S1P) as major contributor to T-cell chemotaxis to the brain during hypertension-associated neuro-inflammation and cognitive impairment. Using Western blotting, flow cytometry and mass spectrometry approaches, we show that hypertension stimulates a sphingosine kinase 1 (SphK1)-dependent increase of cerebral S1P concentrations in a mouse model of angiotensin II (AngII)-induced hypertension. The development of a distinct S1P gradient between circulating blood and brain tissue associates to elevated CD3+ T-cell numbers in the brain. Inhibition of S1P1-guided T-cell chemotaxis with the S1P receptor modulator FTY720 protects from augmentation of brain CD3 expression and the development of memory deficits in hypertensive WT mice. In conclusion, our data highlight a new approach to the understanding of hypertension-associated inflammation in degenerative processes of the brain during disease progression. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessArticle
Effect of Cyclic Stretch on Vascular Endothelial Cells and Abdominal Aortic Aneurysm (AAA): Role in the Inflammatory Response
Int. J. Mol. Sci. 2019, 20(2), 287; https://doi.org/10.3390/ijms20020287
Received: 18 December 2018 / Revised: 8 January 2019 / Accepted: 9 January 2019 / Published: 12 January 2019
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Abstract
Abdominal aortic aneurysm (AAA) is a focal dilatation of the aorta, caused by both genetic and environmental factors. Although vascular endothelium plays a key role in AAA progression, the biological mechanisms underlying the mechanical stress involvement are only partially understood. In this study, [...] Read more.
Abdominal aortic aneurysm (AAA) is a focal dilatation of the aorta, caused by both genetic and environmental factors. Although vascular endothelium plays a key role in AAA progression, the biological mechanisms underlying the mechanical stress involvement are only partially understood. In this study, we developed an in vitro model to characterize the role of mechanical stress as a potential trigger of endothelial deregulation in terms of inflammatory response bridging between endothelial cells (ECs), inflammatory cells, and matrix remodeling. In AAA patients, data revealed different degrees of calcification, inversely correlated with wall stretching and also with inflammation and extracellular matrix degradation. In order to study the role of mechanical stimulation, endothelial cell line (EA.hy926) has been cultured in healthy (10% strain) and pathological (5% strain) dynamic conditions using a bioreactor. In presence of tumor necrosis factor alpha (TNF-α), high levels of matrix metalloproteinase-9 (MMP-9) expression and inflammation are obtained, while mechanical stimulation significantly counteracts the TNF-α effects. Moreover, physiological deformation also plays a significant role in the control of the oxidative stress. Overall our findings indicate that, due to wall calcification, in AAA there is a significant change in terms of decreased wall stretching. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessArticle
Essential Role of Endothelial MCPIP in Vascular Integrity and Post-Ischemic Remodeling
Int. J. Mol. Sci. 2019, 20(1), 172; https://doi.org/10.3390/ijms20010172
Received: 17 December 2018 / Revised: 28 December 2018 / Accepted: 29 December 2018 / Published: 5 January 2019
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Abstract
MCP-1-induced protein (MCPIP, also known as Zc3h12a or Regnase-1), a newly identified suppressor of cytokine signaling, is expressed in endothelial cells (ECs). To investigate the role of endothelial MCPIP in vascular homeostasis and function, we deleted the MCPIP gene specifically in ECs using [...] Read more.
MCP-1-induced protein (MCPIP, also known as Zc3h12a or Regnase-1), a newly identified suppressor of cytokine signaling, is expressed in endothelial cells (ECs). To investigate the role of endothelial MCPIP in vascular homeostasis and function, we deleted the MCPIP gene specifically in ECs using the Cre-LoxP system. EC-specific MCPIP deletion resulted in systemic inflammation, increased vessel permeability, edema, thrombus formation, and premature death in mice. Serum levels of cytokines, chemokines, and biomarkers of EC dysfunction were significantly elevated in these mice. Upon lipopolysaccharide (LPS) challenge, mice with EC-specific MCPIP depletion were highly susceptible to LPS-induced death. When subjected to ischemia, these mice showed defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia. In aortic ring cultures, the MCPIP-deficient ECs displayed significantly impaired vessel sprouting and tube elongation. Mechanistically, silencing of MCPIP by small interfering RNAs in cultured ECs enhanced NF-κΒ activity and dysregulated synthesis of microRNAs linked with elevated cytokines and biomarkers of EC dysfunction. Collectively, these results establish that constitutive expression of MCPIP in ECs is essential to maintaining endothelial homeostasis and function by serving as a key negative feedback regulator that keeps the inflammatory signaling suppressed. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Review

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Open AccessReview
Cross-Talk between Neurohormonal Pathways and the Immune System in Heart Failure: A Review of the Literature
Int. J. Mol. Sci. 2019, 20(7), 1698; https://doi.org/10.3390/ijms20071698
Received: 12 March 2019 / Revised: 1 April 2019 / Accepted: 2 April 2019 / Published: 5 April 2019
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Abstract
Heart failure is a complex clinical syndrome involving a multitude of neurohormonal pathways including the renin-angiotensin-aldosterone system, sympathetic nervous system, and natriuretic peptides system. It is now emerging that neurohumoral mechanisms activated during heart failure, with both preserved and reduced ejection fraction, modulate [...] Read more.
Heart failure is a complex clinical syndrome involving a multitude of neurohormonal pathways including the renin-angiotensin-aldosterone system, sympathetic nervous system, and natriuretic peptides system. It is now emerging that neurohumoral mechanisms activated during heart failure, with both preserved and reduced ejection fraction, modulate cells of the immune system. Indeed, these cells express angiotensin I receptors, adrenoceptors, and natriuretic peptides receptors. Ang II modulates macrophage polarization, promoting M2 macrophages phenotype, and this stimulation can influence lymphocytes Th1/Th2 balance. β-AR activation in monocytes is responsible for inhibition of free oxygen radicals production, and together with α2-AR can modulate TNF-α receptor expression and TNF-α release. In dendritic cells, activation of β2-AR inhibits IL-12 production, resulting in the inhibition of Th1 and promotion of Th2 differentiation. ANP induces the activation of secretion of superoxide anion in polymorphonucleated cells; reduces TNF-α and nitric oxide secretion in macrophages; and attenuates the exacerbated TH1 responses. BNP in macrophages can stimulate ROS production, up-regulates IL-10, and inhibits IL-12 and TNF-α release by dendritic cells, suggesting an anti-inflammatory cytokines profile induction. Therefore, different neurohormonal-immune cross-talks can determine the phenotype of cardiac remodeling, promoting either favorable or maladaptive responses. This review aims to summarize the available knowledge on neurohormonal modulation of immune responses, providing supportive rational background for further research. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessReview
NFkappaB is a Key Player in the Crosstalk between Inflammation and Cardiovascular Diseases
Int. J. Mol. Sci. 2019, 20(7), 1599; https://doi.org/10.3390/ijms20071599
Received: 19 February 2019 / Revised: 21 March 2019 / Accepted: 26 March 2019 / Published: 30 March 2019
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Abstract
Inflammation is a key mechanism of cardiovascular diseases. It is an essential component of atherosclerosis and a significant risk factor for the development of cardiovascular events. In the crosstalk between inflammation and cardiovascular diseases, the transcription factor NFκB seems to be a key [...] Read more.
Inflammation is a key mechanism of cardiovascular diseases. It is an essential component of atherosclerosis and a significant risk factor for the development of cardiovascular events. In the crosstalk between inflammation and cardiovascular diseases, the transcription factor NFκB seems to be a key player since it is involved in the development and progression of both inflammation and cardiac and vascular damage. In this review, we deal with the recent findings of the role of inflammation in cardiac diseases, focusing, in particular, on NFκB as a functional link. We describe strategies for the therapeutic targeting of NFκB as a potential strategy for the failing heart. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessReview
Periodontal Disease: A Risk Factor for Diabetes and Cardiovascular Disease
Int. J. Mol. Sci. 2019, 20(6), 1414; https://doi.org/10.3390/ijms20061414
Received: 9 February 2019 / Revised: 25 February 2019 / Accepted: 18 March 2019 / Published: 20 March 2019
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Abstract
Periodontitis is a chronic inflammatory disease, initiated by the presence of a bacterial biofilm, called dental plaque, which affects both the periodontal ligaments and bone surrounding teeth. In the last decades, several lines of evidence have supported the existence of a relationship between [...] Read more.
Periodontitis is a chronic inflammatory disease, initiated by the presence of a bacterial biofilm, called dental plaque, which affects both the periodontal ligaments and bone surrounding teeth. In the last decades, several lines of evidence have supported the existence of a relationship between periodontitis and systemic health. For instance, as periodontitis acts within the same chronic inflammatory model seen in cardiovascular disease (CVD), or other disorders, such as diabetes, several studies have suggested the existence of a bi-directional link between periodontal health and these pathologies. For instance, people with diabetes are more susceptible to infections and are more likely to suffer from periodontitis than people without this syndrome. Analogously, it is now evident that cardiac disorders are worsened by periodontitis, both experimentally and in humans. For all these reasons, it is very plausible that preventing periodontitis has an impact on the onset or progression of CVD and diabetes. On these grounds, in this review, we have provided an updated account on the current knowledge concerning periodontal disease and the adverse effects exerted on the cardiovascular system health and diabetes, informing readers on the most recent preclinical studies and epidemiological evidence. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessReview
The microRNAs Regulating Vascular Smooth Muscle Cell Proliferation: A Minireview
Int. J. Mol. Sci. 2019, 20(2), 324; https://doi.org/10.3390/ijms20020324
Received: 5 December 2018 / Revised: 1 January 2019 / Accepted: 2 January 2019 / Published: 14 January 2019
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Abstract
Vascular smooth muscle cell (VSMC) proliferation plays a critical role in atherosclerosis. At the beginning of the pathologic process of atherosclerosis, irregular VSMC proliferation promotes plaque formation, but in advanced plaques VSMCs are beneficial, promoting the stability and preventing rupture of the fibrous [...] Read more.
Vascular smooth muscle cell (VSMC) proliferation plays a critical role in atherosclerosis. At the beginning of the pathologic process of atherosclerosis, irregular VSMC proliferation promotes plaque formation, but in advanced plaques VSMCs are beneficial, promoting the stability and preventing rupture of the fibrous cap. Recent studies have demonstrated that microRNAs (miRNAs) expressed in the vascular system are involved in the control of VSMC proliferation. This review summarizes recent findings on the miRNAs in the regulation of VSMC proliferation, including miRNAs that exhibit the inhibition or promotion of VSMC proliferation, and their targets mediating the regulation of VSMC proliferation. Up to now, most of the studies were performed only in cultured VSMC. While the modulation of miRNAs is emerging as a promising strategy for the regulation of VSMC proliferation, most of the effects of miRNAs and their targets in vivo require further investigation. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessReview
TRIMming down to TRIM37: Relevance to Inflammation, Cardiovascular Disorders, and Cancer in MULIBREY Nanism
Int. J. Mol. Sci. 2019, 20(1), 67; https://doi.org/10.3390/ijms20010067
Received: 23 October 2018 / Revised: 12 December 2018 / Accepted: 19 December 2018 / Published: 24 December 2018
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Abstract
TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review, we focus on TRIM37 in the normal cell and in pathological conditions, with an emphasis on the [...] Read more.
TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review, we focus on TRIM37 in the normal cell and in pathological conditions, with an emphasis on the MULIBREY (MUscle-LIver-BRain-EYe) genetic disorder caused by TRIM37 mutations. TRIM37 is characterized by the presence of a RING domain, B-box motifs, and a coiled-coil region, and its C-terminal part includes the MATH domain specific to TRIM37. MULIBREY nanism is a rare autosomal recessive caused by TRIM37 mutations and characterized by severe pre- and postnatal growth failure. Constrictive pericarditis is the most serious anomaly of the disease and is present in about 20% of patients. The patients have a deregulation of glucose and lipid metabolism, including type 2 diabetes, fatty liver, and hypertension. Puzzlingly, MULIBREY patients, deficient for TRIM37, are plagued with numerous tumors. Among non-MULIBREY patients affected by cancer, a wide variety of cancers are associated with an overexpression of TRIM37. This suggests that normal cells need an optimal equilibrium in TRIM37 expression. Finding a way to keep that balance could lead to potential innovative drugs for MULIBREY nanism, including heart condition and carcinogenesis treatment. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessReview
Novel Insights into the Crosstalk between Mineralocorticoid Receptor and G Protein-Coupled Receptors in Heart Adverse Remodeling and Disease
Int. J. Mol. Sci. 2018, 19(12), 3764; https://doi.org/10.3390/ijms19123764
Received: 8 November 2018 / Revised: 21 November 2018 / Accepted: 23 November 2018 / Published: 27 November 2018
Cited by 1 | PDF Full-text (583 KB) | HTML Full-text | XML Full-text
Abstract
The mineralocorticoid hormone aldosterone regulates sodium and potassium homeostasis but also adversely modulates the maladaptive process of cardiac adverse remodeling post-myocardial infarction. Through activation of its mineralocorticoid receptor (MR), a classic steroid hormone receptor/transcription factor, aldosterone promotes inflammation and fibrosis of the heart, [...] Read more.
The mineralocorticoid hormone aldosterone regulates sodium and potassium homeostasis but also adversely modulates the maladaptive process of cardiac adverse remodeling post-myocardial infarction. Through activation of its mineralocorticoid receptor (MR), a classic steroid hormone receptor/transcription factor, aldosterone promotes inflammation and fibrosis of the heart, the vasculature, and the kidneys. This is why MR antagonists reduce morbidity and mortality of heart disease patients and are part of the mainstay pharmacotherapy of advanced human heart failure. A plethora of animal studies using cell type–specific targeting of the MR gene have established the importance of MR signaling and function in cardiac myocytes, vascular endothelial and smooth muscle cells, renal cells, and macrophages. In terms of its signaling properties, the MR is distinct from nuclear receptors in that it has, in reality, two physiological hormonal agonists: not only aldosterone but also cortisol. In fact, in several tissues, including in the myocardium, cortisol is the primary hormone activating the MR. There is a considerable amount of evidence indicating that the effects of the MR in each tissue expressing it depend on tissue- and ligand-specific engagement of molecular co-regulators that either activate or suppress its transcriptional activity. Identification of these co-regulators for every ligand that interacts with the MR in the heart (and in other tissues) is of utmost importance therapeutically, since it can not only help elucidate fully the pathophysiological ramifications of the cardiac MR’s actions, but also help design and develop novel better MR antagonist drugs for heart disease therapy. Among the various proteins the MR interacts with are molecules involved in cardiac G protein-coupled receptor (GPCR) signaling. This results in a significant amount of crosstalk between GPCRs and the MR, which can affect the latter’s activity dramatically in the heart and in other cardiovascular tissues. This review summarizes the current experimental evidence for this GPCR-MR crosstalk in the heart and discusses its pathophysiological implications for cardiac adverse remodeling as well as for heart disease therapy. Novel findings revealing non-conventional roles of GPCR signaling molecules, specifically of GPCR-kinase (GRK)-5, in cardiac MR regulation are also highlighted. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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