The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Nikolaos G. Frangogiannis - One of the best experts on this subject based on the ideXlab platform.
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Cardiac Fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities
Molecular Aspects of Medicine, 2018Co-Authors: Nikolaos G. FrangogiannisAbstract:Cardiac Fibrosis is a common pathophysiologic companion of most myocardial diseases, and is associated with systolic and diastolic dysfunction, arrhythmogenesis, and adverse outcome. Because the adult mammalian heart has negligible regenerative capacity, death of a large number of cardiomyocytes results in reparative Fibrosis, a process that is critical for preservation of the structural integrity of the infarcted ventricle. On the other hand, pathophysiologic stimuli, such as pressure overload, volume overload, metabolic dysfunction, and aging may cause interstitial and perivascular Fibrosis in the absence of infarction. Activated myofibroblasts are the main effector cells in Cardiac Fibrosis; their expansion following myocardial injury is primarily driven through activation of resident interstitial cell populations. Several other cell types, including cardiomyocytes, endothelial cells, pericytes, macrophages, lymphocytes and mast cells may contribute to the fibrotic process, by producing proteases that participate in matrix metabolism, by secreting fibrogenic mediators and matricellular proteins, or by exerting contact-dependent actions on fibroblast phenotype. The mechanisms of induction of fibrogenic signals are dependent on the type of primary myocardial injury. Activation of neurohumoral pathways stimulates fibroblasts both directly, and through effects on immune cell populations. Cytokines and growth factors, such as Tumor Necrosis Factor-α Interleukin (IL)-1, IL-10, chemokines, members of the Transforming Growth Factor-β family, IL-11, and Platelet-Derived Growth Factors are secreted in the Cardiac interstitium and play distinct roles in activating specific aspects of the fibrotic response. Secreted fibrogenic mediators and matricellular proteins bind to cell surface receptors in fibroblasts, such as cytokine receptors, integrins, syndecans and CD44, and transduce intracellular signaling cascades that regulate genes involved in synthesis, processing and metabolism of the extracellular matrix. Endogenous pathways involved in negative regulation of Fibrosis are critical for Cardiac repair and may protect the myocardium from excessive fibrogenic responses. Due to the reparative nature of many forms of Cardiac Fibrosis, targeting fibrotic remodeling following myocardial injury poses major challenges. Development of effective therapies will require careful dissection of the cell biological mechanisms, study of the functional consequences of fibrotic changes on the myocardium, and identification of heart failure patient subsets with overactive fibrotic responses.
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diabetes associated Cardiac Fibrosis cellular effectors molecular mechanisms and therapeutic opportunities
Journal of Molecular and Cellular Cardiology, 2016Co-Authors: Ilaria Russo, Nikolaos G. FrangogiannisAbstract:Both type 1 and type 2 diabetes are associated with Cardiac Fibrosis that may reduce myocardial compliance, contribute to the pathogenesis of heart failure, and trigger arrhythmic events. Diabetes-associated Fibrosis is mediated by activated Cardiac fibroblasts, but may also involve fibrogenic actions of macrophages, cardiomyocytes and vascular cells. The molecular basis responsible for Cardiac Fibrosis in diabetes remains poorly understood. Hyperglycemia directly activates a fibrogenic program, leading to accumulation of advanced glycation end-products (AGEs) that crosslink extracellular matrix proteins, and transduce fibrogenic signals through reactive oxygen species generation, or through activation of Receptor for AGEs (RAGE)-mediated pathways. Pro-inflammatory cytokines and chemokines may recruit fibrogenic leukocyte subsets in the Cardiac interstitium. Activation of transforming growth factor-β/Smad signaling may activate fibroblasts inducing deposition of structural extracellular matrix proteins and matricellular macromolecules. Adipokines, endothelin-1 and the renin-angiotensin-aldosterone system have also been implicated in the diabetic myocardium. This manuscript reviews our current understanding of the cellular effectors and molecular pathways that mediate Fibrosis in diabetes. Based on the pathophysiologic mechanism, we propose therapeutic interventions that may attenuate the diabetes-associated fibrotic response and discuss the challenges that may hamper clinical translation.
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The pathogenesis of Cardiac Fibrosis
Cellular and Molecular Life Sciences, 2014Co-Authors: Ping Kong, Panagiota Christia, Nikolaos G. FrangogiannisAbstract:Cardiac Fibrosis is characterized by net accumulation of extracellular matrix proteins in the Cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many Cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of Cardiac Fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in Cardiac Fibrosis. Both experimental and clinical evidence suggests that Cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of Cardiac Fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.
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aging and Cardiac Fibrosis
Aging and Disease, 2011Co-Authors: Anna Biernacka, Nikolaos G. FrangogiannisAbstract:The aging heart is characterized by morphological and structural changes that lead to its functional decline and are associated with diminished ability to meet increased demand. Extensive evidence, derived from both clinical and experimental studies suggests that the aging heart undergoes fibrotic remodeling. Age-dependent accumulation of collagen in the heart leads to progressive increase in ventricular stiffness and impaired diastolic function. Increased mechanical load, due to reduced arterial compliance, and direct senescence-associated fibrogenic actions appear to be implicated in the pathogenesis of Cardiac Fibrosis in the elderly. Evolving evidence suggests that activation of several distinct molecular pathways may contribute to age-related fibrotic Cardiac remodeling. Reactive oxygen species, chemokine-mediated recruitment of mononuclear cells and fibroblast progenitors, transforming growth factor (TGF)-β activation, endothelin-1 and angiotensin II signaling mediate interstitial and perivascular Fibrosis in the senescent heart. Reduced collagen degradation may be more important than increased de novo synthesis in the pathogenesis of aging-associated Fibrosis. In contrast to the baseline activation of fibrogenic pathways in the senescent heart, aging is associated with an impaired reparative response to Cardiac injury and defective activation of reparative fibroblasts in response to growth factors. Because these reparative defects result in defective scar formation, senescent hearts are prone to adverse dilative remodeling following myocardial infarction. Understanding the pathogenesis of interstitial Fibrosis in the aging heart and dissecting the mechanisms responsible for age-associated healing defects following Cardiac injury are critical in order to design new strategies for prevention of adverse remodeling and heart failure in elderly patients.
Harry C. J. Ottenheijm - One of the best experts on this subject based on the ideXlab platform.
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Fadrozole reverses Cardiac Fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone.
Endocrinology, 2007Co-Authors: Monica Minnaard-huiban, Judith M. A. Emmen, Luc Roumen, Ilona P. E. Beugels, Géraldine M. S. Cohuet, Helma Van Essen, Eveline Ruijters, Koen Pieterse, Paj Peter Hilbers, Harry C. J. OttenheijmAbstract:Reversal of Cardiac Fibrosis is a major determinant of the salutary effects of mineralocorticoid receptor antagonists in heart failure. Recently, R-fadrozole was coined as an aldosterone biosynthesis inhibitor, offering an appealing alternative to mineralocorticoid receptor antagonists to block aldosterone action. The present study aimed to evaluate the effects of R- and S-fadrozole on plasma aldosterone and urinary aldosterone excretion rate and to compare their effectiveness vs. the mineralocorticoid receptor antagonist potassium canrenoate to reverse established Cardiac Fibrosis. Male lean spontaneously hypertensive heart failure (SHHF) rats (40 wk) were treated for 8 wk by sc infusions of low (0.24 mg/kg·d) or high (1.2 mg/kg·d) doses of R- or S-fadrozole or by potassium canrenoate via drinking water (7.5 mg/kg·d). At the high dose, plasma aldosterone levels were decreased similarly by R- and S-fadrozole, whereas urinary aldosterone excretion rate was reduced only by S-fadrozole. In contrast, whereas ...
Monica Minnaard-huiban - One of the best experts on this subject based on the ideXlab platform.
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Fadrozole reverses Cardiac Fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone.
Endocrinology, 2007Co-Authors: Monica Minnaard-huiban, Judith M. A. Emmen, Luc Roumen, Ilona P. E. Beugels, Géraldine M. S. Cohuet, Helma Van Essen, Eveline Ruijters, Koen Pieterse, Paj Peter Hilbers, Harry C. J. OttenheijmAbstract:Reversal of Cardiac Fibrosis is a major determinant of the salutary effects of mineralocorticoid receptor antagonists in heart failure. Recently, R-fadrozole was coined as an aldosterone biosynthesis inhibitor, offering an appealing alternative to mineralocorticoid receptor antagonists to block aldosterone action. The present study aimed to evaluate the effects of R- and S-fadrozole on plasma aldosterone and urinary aldosterone excretion rate and to compare their effectiveness vs. the mineralocorticoid receptor antagonist potassium canrenoate to reverse established Cardiac Fibrosis. Male lean spontaneously hypertensive heart failure (SHHF) rats (40 wk) were treated for 8 wk by sc infusions of low (0.24 mg/kg·d) or high (1.2 mg/kg·d) doses of R- or S-fadrozole or by potassium canrenoate via drinking water (7.5 mg/kg·d). At the high dose, plasma aldosterone levels were decreased similarly by R- and S-fadrozole, whereas urinary aldosterone excretion rate was reduced only by S-fadrozole. In contrast, whereas ...
Peipei Wang - One of the best experts on this subject based on the ideXlab platform.
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microrna 221 inhibits latent tgf β1 activation through targeting thrombospondin 1 to attenuate kidney failure induced Cardiac Fibrosis
Molecular therapy. Nucleic acids, 2020Co-Authors: Yue Zhou, A M Richards, Peipei WangAbstract:Kidney failure (KF) is associated with Cardiac Fibrosis and significantly increased mortality in heart failure. Thrombospondin-1 (TSP1), a key regulator of latent transforming growth factor-β1 (L-TGF-β1) activation, is a predicted target of miR-221. We hypothesized miR-221 attenuates severe KF-associated Cardiac Fibrosis via targeting of Thbs1 with subsequent inhibition of L-TGF-β1 activation. Rat Cardiac fibroblasts (cFB) were isolated and transfected with microRNA-221 (miR-221) mimics or mimic control (miR-221 and MC) with or without exposure to L-TGF-β1. We demonstrate miR-221 downregulates Thbs1 via direct 3′ untranslated region (3′ UTR) targeting with consequent inhibition of L-TGF-β1 activation in cFB as proven by the significant reduction of myofibroblast activation, collagen secretion, TGF-β1 signaling, TSP1 secretion, and TGF-β1 bioactivity measured by Pai1 promoter reporter. The 5/6 nephrectomy (Nx) model of Cardiac Fibrosis was used to test the in vivo therapeutic efficacy of miR-221 (i.v. 1 mg/kg ×3). miR-221 significantly inhibited Nx-induced upregulation of TSP1 and p-SMAD3 in the heart at day-7 and reduced Cardiac Fibrosis (picro-sirius), improved Cardiac function (±dP/dt), and improved 8-week survival rate (60% versus 36%; p = 0.038). miR-221 mimic treatment improved survival and reduced Cardiac Fibrosis in a model of severe KF. miR-221 is a therapeutic target to address Cardiac Fibrosis originating from renal disease and other causes.
Seock Won Youn - One of the best experts on this subject based on the ideXlab platform.
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snail as a potential target molecule in Cardiac Fibrosis paracrine action of endothelial cells on fibroblasts through snail and ctgf axis
Molecular Therapy, 2013Co-Authors: Seock Won YounAbstract:Ischemia/reperfusion (I/R) injury to myocardium induces death of cardiomyocytes and destroys the vasculature, leading to Cardiac Fibrosis that is mainly mediated by the transdifferentiation of fibroblasts to myofibroblasts and the collagen deposition. Snail involvement in Fibrosis is well known; however, the contribution of Snail to Cardiac Fibrosis during I/R injury and its underlying mechanisms have not been defined. We showed that I/R injury to mouse hearts significantly increases the expression of Snail. An in vitro hypoxia/reoxygenation (Hy/Reoxy) experiment showed that the cell source of Snail induction is endothelial cells rather than Cardiac fibroblasts (cFibroblasts) or cardiomyoblasts. When Snail was overexpressed in endothelial cells, they underwent endothelial-to-mesenchymal transition (EndMT) but showed very poor capacity for collagen synthesis. Instead, reoxygenation- or Snail overexpression-mediated EndMT-like cells noticeably stimulated transdifferentiation of fibroblasts to myofibroblasts via secretion of connective tissue growth factor (CTGF). The injection of a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, a selective Snail inhibitor, remarkably suppressed collagen deposition and Cardiac Fibrosis in mouse I/R injury, and significantly improved Cardiac function and reduced Snail and CTGF expression in vivo. Our findings suggested a new mechanism of cell-to-cell communication between EndMT-like cells and fibroblasts for Fibrosis induction and implicated Snail as a potential target molecule in Cardiac Fibrosis after I/R injury.