International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Inflammation and Cardiovascular Diseases: The Most Recent Findings

by Daniela Sorriento and Guido Iaccarino

Int. J. Mol. Sci. 2019, 20(16), 3879; https://doi.org/10.3390/ijms20163879 - 9 Aug 2019

Cited by 110 | Viewed by 4445

Abstract

The series of reactive biological events that we identify as inflammation has been investigated in recent years and unveiled as an important mechanism for regeneration. The study of the underlying complexity has been boosted by new technological innovation in research and allowed the [...] Read more.

The series of reactive biological events that we identify as inflammation has been investigated in recent years and unveiled as an important mechanism for regeneration. The study of the underlying complexity has been boosted by new technological innovation in research and allowed the identification of inflammatory responses as the basis of diseases that were considered degenerative rather than regenerative in nature. This is the case for cardiovascular diseases, from the organ damage that follows an acute event to the damage of target organs exposed to chronic risk factors. This editorial explores innovative aspects of inflammation in the setup of cardiovascular risk factors and diseases. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)

Research

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12 pages, 1211 KiB

Open AccessArticle

Cardiosomal microRNAs Are Essential in Post-Infarction Myofibroblast Phenoconversion

by Marco B. Morelli, Jun Shu, Celestino Sardu, Alessandro Matarese and Gaetano Santulli

Int. J. Mol. Sci. 2020, 21(1), 201; https://doi.org/10.3390/ijms21010201 - 27 Dec 2019

Cited by 66 | Viewed by 4019

Abstract

The inclusion of microRNAs (miRNAs) in extracellular microvesicles/exosomes (named cardiosomes when deriving from cardiomyocytes) allows their active transportation and ensures cell-cell communication. We hypothesize that cardiosomal miRNAs play a pivotal role in the activation of myofibroblasts following ischemic injury. Using a murine model [...] Read more.

The inclusion of microRNAs (miRNAs) in extracellular microvesicles/exosomes (named cardiosomes when deriving from cardiomyocytes) allows their active transportation and ensures cell-cell communication. We hypothesize that cardiosomal miRNAs play a pivotal role in the activation of myofibroblasts following ischemic injury. Using a murine model of myocardial infarction (MI), we tested our hypothesis by measuring in isolated fibroblasts and cardiosomes the expression levels of a set of miRNAs, which are upregulated in cardiomyocytes post-MI and involved in myofibroblast phenoconversion. We found that miR-195 was significantly upregulated in cardiosomes and in fibroblasts isolated after MI compared with SHAM conditions. Moreover, primary isolated cardiac fibroblasts were activated both when incubated with cardiosomes isolated from ischemic cardiomyocytes and when cultured in conditioned medium of post-MI cardiomyocytes, whereas no significant effect was observed following incubation with cardiosomes or medium from sham cardiomyocytes. Taken together, our findings indicate for the first time that a cardiomyocyte-specific miRNA, transferred to fibroblasts in form of exosomal cargo, is crucial in the activation of myofibroblasts. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)

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15 pages, 2593 KiB

Open AccessArticle

CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy

by Thomas J. LaRocca, Perry Altman, Andrew A. Jarrah, Ron Gordon, Edward Wang, Lahouaria Hadri, Mark W. Burke, Georges E. Haddad, Roger J. Hajjar and Sima T. Tarzami

Int. J. Mol. Sci. 2019, 20(9), 2267; https://doi.org/10.3390/ijms20092267 - 8 May 2019

Cited by 21 | Viewed by 4990

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/dt_max, 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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10 pages, 712 KiB

Open AccessArticle

Inflammatory, Serological and Vascular Determinants of Cardiovascular Disease in Systemic Lupus Erythematosus Patients

by Valentina Mercurio, Antonio Lobasso, Letizia Barbieri, Paolo Parrella, Deasy Ciervo, Bianca Liccardo, Domenico Bonaduce, Carlo G. Tocchetti, Amato De Paulis and Francesca W. Rossi

Int. J. Mol. Sci. 2019, 20(9), 2154; https://doi.org/10.3390/ijms20092154 - 30 Apr 2019

Cited by 27 | Viewed by 3512

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 (AIx@75), 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 AIx@75 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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17 pages, 961 KiB

Open AccessArticle

Superantigenic Activation of Human Cardiac Mast Cells

by Gilda Varricchi, Stefania Loffredo, Francesco Borriello, Antonio Pecoraro, Felice Rivellese, Arturo Genovese, Giuseppe Spadaro and Gianni Marone

Int. J. Mol. Sci. 2019, 20(8), 1828; https://doi.org/10.3390/ijms20081828 - 12 Apr 2019

Cited by 43 | Viewed by 3454

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 V_H3⁺ 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 V_H3 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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17 pages, 2577 KiB

Open AccessArticle

Antidiabetic and Cardioprotective Effects of Pharmacological Inhibition of GRK2 in db/db Mice

by Ersilia Cipolletta, Jessica Gambardella, Antonella Fiordelisi, Carmine Del Giudice, Eugenio Di Vaia, Michele Ciccarelli, Marina Sala, Pietro Campiglia, Enrico Coscioni, Bruno Trimarco, Daniela Sorriento and Guido Iaccarino

Int. J. Mol. Sci. 2019, 20(6), 1492; https://doi.org/10.3390/ijms20061492 - 25 Mar 2019

Cited by 23 | Viewed by 4995

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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13 pages, 1319 KiB

Open AccessArticle

Deletion of Osteopontin Enhances β₂-Adrenergic Receptor-Dependent Anti-Fibrotic Signaling in Cardiomyocytes

by Celina M. Pollard, Victoria L. Desimine, Shelby L. Wertz, Arianna Perez, Barbara M. Parker, Jennifer Maning, Katie A. McCrink, Lina A. Shehadeh and Anastasios Lymperopoulos

Int. J. Mol. Sci. 2019, 20(6), 1396; https://doi.org/10.3390/ijms20061396 - 20 Mar 2019

Cited by 39 | Viewed by 4320

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 G_αs 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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14 pages, 1641 KiB

Open AccessCommunication

T-Cell Accumulation in the Hypertensive Brain: A Role for Sphingosine-1-Phosphate-Mediated Chemotaxis

by Nicholas Don-Doncow, Lotte Vanherle, Yun Zhang and Anja Meissner

Int. J. Mol. Sci. 2019, 20(3), 537; https://doi.org/10.3390/ijms20030537 - 28 Jan 2019

Cited by 18 | Viewed by 4290

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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16 pages, 3546 KiB

Open AccessArticle

Effect of Cyclic Stretch on Vascular Endothelial Cells and Abdominal Aortic Aneurysm (AAA): Role in the Inflammatory Response

by Martina Ramella, Giulia Bertozzi, Luca Fusaro, Maria Talmon, Marcello Manfredi, Marta Calvo Catoria, Francesco Casella, Carla Maria Porta, Renzo Boldorini, Luigia Grazia Fresu, Emilio Marengo and Francesca Boccafoschi

Int. J. Mol. Sci. 2019, 20(2), 287; https://doi.org/10.3390/ijms20020287 - 12 Jan 2019

Cited by 16 | Viewed by 5247

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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18 pages, 3644 KiB

Open AccessArticle

Essential Role of Endothelial MCPIP in Vascular Integrity and Post-Ischemic Remodeling

by Zhuqing Jin, Jianli Niu, Nidhi Kapoor, Jian Liang, Edilu Becerra and Pappachan E. Kolattukudy

Int. J. Mol. Sci. 2019, 20(1), 172; https://doi.org/10.3390/ijms20010172 - 5 Jan 2019

Cited by 12 | Viewed by 3845

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

Jump to: Editorial, Research

18 pages, 2168 KiB

Open AccessReview

Cross-Talk between Neurohormonal Pathways and the Immune System in Heart Failure: A Review of the Literature

by Elena De Angelis, Michela Pecoraro, Maria Rosaria Rusciano, Michele Ciccarelli and Ada Popolo

Int. J. Mol. Sci. 2019, 20(7), 1698; https://doi.org/10.3390/ijms20071698 - 5 Apr 2019

Cited by 37 | Viewed by 6357

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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17 pages, 1848 KiB

Open AccessReview

NFkappaB is a Key Player in the Crosstalk between Inflammation and Cardiovascular Diseases

by Antonella Fiordelisi, Guido Iaccarino, Carmine Morisco, Enrico Coscioni and Daniela Sorriento

Int. J. Mol. Sci. 2019, 20(7), 1599; https://doi.org/10.3390/ijms20071599 - 30 Mar 2019

Cited by 156 | Viewed by 5680

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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14 pages, 646 KiB

Open AccessReview

Periodontal Disease: A Risk Factor for Diabetes and Cardiovascular Disease

by Daniela Liccardo, Alessandro Cannavo, Gianrico Spagnuolo, Nicola Ferrara, Antonio Cittadini, Carlo Rengo and Giuseppe Rengo

Int. J. Mol. Sci. 2019, 20(6), 1414; https://doi.org/10.3390/ijms20061414 - 20 Mar 2019

Cited by 283 | Viewed by 27213

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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15 pages, 875 KiB

Open AccessReview

The microRNAs Regulating Vascular Smooth Muscle Cell Proliferation: A Minireview

by Dongdong Wang and Atanas G. Atanasov

Int. J. Mol. Sci. 2019, 20(2), 324; https://doi.org/10.3390/ijms20020324 - 14 Jan 2019

Cited by 67 | Viewed by 10014

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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14 pages, 2000 KiB

Open AccessReview

TRIMming down to TRIM37: Relevance to Inflammation, Cardiovascular Disorders, and Cancer in MULIBREY Nanism

by Benjamin Brigant, Valérie Metzinger-Le Meuth, Jacques Rochette and Laurent Metzinger

Int. J. Mol. Sci. 2019, 20(1), 67; https://doi.org/10.3390/ijms20010067 - 24 Dec 2018

Cited by 45 | Viewed by 6499

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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13 pages, 583 KiB

Open AccessReview

Novel Insights into the Crosstalk between Mineralocorticoid Receptor and G Protein-Coupled Receptors in Heart Adverse Remodeling and Disease

by Barbara M. Parker, Shelby L. Wertz, Celina M. Pollard, Victoria L. Desimine, Jennifer Maning, Katie A. McCrink and Anastasios Lymperopoulos

Int. J. Mol. Sci. 2018, 19(12), 3764; https://doi.org/10.3390/ijms19123764 - 27 Nov 2018

Cited by 29 | Viewed by 6520

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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