scholarly journals EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling

2017 ◽  
Vol 121 (6) ◽  
pp. 617-627 ◽  
Author(s):  
Sheng-an Su ◽  
Du Yang ◽  
Yue Wu ◽  
Yao Xie ◽  
Wei Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Intramyocardial Injection

Rationale: Cardiac fibrosis is a common feature in left ventricular remodeling that leads to heart failure, regardless of the cause. EphrinB2 (erythropoietin-producing hepatoma interactor B2), a pivotal bidirectional signaling molecule ubiquitously expressed in mammals, is crucial in angiogenesis during development and disease progression. Recently, EphrinB2 was reported to protect kidneys from injury-induced fibrogenesis. However, its role in cardiac fibrosis remains to be clarified. Objective: We sought to determine the role of EphrinB2 in cardiac fibrosis and the underlying mechanisms during the pathological remodeling process. Methods and Results: EphrinB2 was highly expressed in the myocardium of patients with advanced heart failure, as well as in mouse models of myocardial infarction and cardiac hypertrophy induced by angiotensin II infusion, which was accompanied by myofibroblast activation and collagen fiber deposition. In contrast, intramyocardial injection of lentiviruses carrying EphrinB2-shRNA ameliorated cardiac fibrosis and improved cardiac function in mouse model of myocardial infarction. Furthermore, in vitro studies in cultured cardiac fibroblasts demonstrated that EphrinB2 promoted the differentiation of cardiac fibroblasts into myofibroblasts in normoxic and hypoxic conditions. Mechanistically, the profibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 (signal transducer and activator of transcription 3) and TGF-β (transforming growth factor-β)/Smad3 (mothers against decapentaplegic homolog 3) signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3 and identified that the MAD homology 2 domain of Smad3 and the coil–coil domain and DNA-binding domain of Stat3 mediated the interaction. Conclusions: This study uncovered a previously unrecognized profibrotic role of EphrinB2 in cardiac fibrosis, which is achieved through the interaction of Stat3 with TGF-β/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.

Role of oxidative stress in left ventricular remodeling and heart failure after myocardial infarction

1999 ◽  
Vol 5 (3) ◽  
pp. 79
Author(s):  
Shintaro Kinugawa ◽  
Hiroyuki Tsutsui ◽  
Tomomi Ide ◽  
Hideo Ustumi ◽  
Nobuhiro Suematsu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

scholarly journals MicroRNAs—The Heart of Post-Myocardial Infarction Remodeling

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1675
Author(s):  
Liana Maries ◽  
Cătălin Marian ◽  
Raluca Sosdean ◽  
Flavia Goanta ◽  
Ioan Ovidiu Sirbu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Left Ventricular

Myocardial infarction (MI) is one of the most frequent cardiac emergencies, with significant potential for mortality. One of the major challenges of the post-MI healing response is that replacement fibrosis could lead to left ventricular remodeling (LVR) and heart failure (HF). This process involves canonical and non-canonical transforming growth factor-beta (TGF-β) signaling pathways translating into an intricate activation of cardiac fibroblasts and disproportionate collagen synthesis. Accumulating evidence has indicated that microRNAs (miRNAs) significantly contribute to the modulation of these signaling pathways. This review summarizes the recent updates regarding the molecular mechanisms underlying the role of the over 30 miRNAs involved in post-MI LVR. In addition, we compare the contradictory roles of several multifunctional miRNAs and highlight their potential use in pressure overload and ischemia-induced fibrosis. Finally, we discuss their attractive role as prognostic biomarkers for HF, highlighting the most relevant human trials involving these miRNAs.

Predictors of Left Ventricular Remodeling Post Acute Myocardial Infarction. Protocol for a Clinical Study

2019 ◽  
Vol 4 (3) ◽  
pp. 120-123
Author(s):  
Ioana Cîrneală ◽  
Diana Opincariu ◽  
István Kovács ◽  
Monica Chițu ◽  
Imre Benedek
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Speckle Tracking ◽  
Ventricular Remodeling ◽  
Speckle Tracking Echocardiography ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Serum Biomarkers ◽  
Remodeling Index

Abstract Heart failure is a clinical syndrome that appears as a consequence of a structural disease, and the most common cause of left ventricular systolic dysfunction results from myocardial ischemia. Cardiac remodeling and neuroendocrine activation are the major compensatory mechanisms in heart failure. The main objective of the study is to identify the association between serum biomarkers illustrating the extent of myocardial necrosis (highly sensitive troponin as-says), left ventricular dysfunction (NT-proBNP), and systemic inflammatory response (illustrated via serum levels of hsCRP and interleukins) during the acute phase of a myocardial infarction, and the left ventricular remodeling process at 6 months following the acute event, quantified via speckle tracking echocardiography. The study will include 400 patients diagnosed with acute myocardial infarction without signs and symptoms of heart failure at the time of enrollment that will undergo a complex clinical examination and speckle tracking echocardiography. Serum samples from the peripheral blood will be collected in order to determine the inflammatory serum biomarkers. After 6 months, patients will be divided into 2 groups according to the development of ventricular remodeling, quantified by speckle tracking echocardiography: group 1 will consist of patients with a remodeling index lower than 15%, and group 2 will consist of patients with a remodeling index higher than 15%. All clinical and imaging data obtained at the baseline will be compared between these two groups in order to determine the features associated with a higher risk of deleterious ventricular remodeling and heart failure.

Abstract 865: Gata-4 Is An Angiogenic Survival Factor Of The Infarcted Heart

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Olli Tenhunen ◽  
Hanna Leskinen ◽  
Raisa Serpi ◽  
Jaana Rysä ◽  
Harri Pennanen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Gene Transfer ◽  
Dna Binding ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Therapeutic Interventions ◽  
Cardiac Stem Cells

Recent data suggest that the cardiac-restricted transcription factor GATA-4 is an anti-apoptotic factor required for adaptive responses as well as a key regulator of hypertrophy and hypertrophy-associated genes in the heart. As a leading cause of chronic heart failure, reversal of post-infarction left ventricular remodeling represents an important target for therapeutic interventions. Here we studied the role of GATA-4 as a mediator of post-infarction remodeling. Rats were subjected to experimental myocardial infarction (MI) by ligating the left anterior descending coronary artery (LAD). Ligation of the LAD decreased the DNA binding activity of GATA-4 by 69 % at day 1 after MI (P<0.001, n=7– 8) as assessed by gel mobility shift assays. At 2 weeks the GATA-4 DNA binding was significantly upregulated (2.4-fold, P<0.05, n=7), and returned to baseline at 4 weeks. To determine the functional role of GATA-4, rats underwent LAD ligation followed by peri-infarct intramyocardial delivery of adenoviral vector expressing GATA-4. Hearts treated with the GATA-4 gene transfer exhibited significantly increased ejection fraction (58±5% vs. 38±3% in LacZ-treated control animals with MI, P<0.001, n=8 –9) and fractional shortening (28±3% vs. 16±1%, P<0.001, n=8 –9) 2 weeks after MI. Accordingly, the infarct size was significantly reduced (26±4% vs. 45±4%, P<0.01, n=8 –9). To determine the cardioprotective mechanisms of GATA-4, the number of cardiac stem cells, apoptotic cardiomyocytes and capillaries were assessed. The number of capillaries (59±4/field vs. 48±3/field, P<0.051, n=7– 8) and c-kit positive stem cells (13±5 cells vs. 4±2 cells, P<0.05, n=7– 8) were increased in GATA-4 treated hearts, and a tendency to decreased apoptosis was observed in TUNEL-stained histological sections. These results indicate that the reversal of reduced GATA-4 activity prevents adverse post-infarction remodeling through increased angiogenesis, recruitment of cardiac stem cells and anti-apoptosis. GATA-4-based gene transfer may represent a novel, efficient therapeutic approach for heart failure.

scholarly journals Progression of heart failure after myocardial infarction in the rat

2001 ◽  
Vol 281 (5) ◽  
pp. R1734-R1745 ◽  
Author(s):  
J. Francis ◽  
R. M. Weiss ◽  
S. G. Wei ◽  
A. K. Johnson ◽  
R. B. Felder
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Left Ventricular Remodeling ◽  
Plasma Renin ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple “switching on” of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.

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