Smad3 also regulates the promoter activity of connective tissue growth factor (CTGF), a key mediator of ECM production during cardiac fibrotic remodeling 9. For instance, TGF-β-mediated production of ECM in cardiac fibroblasts is Smad3-dependent 5, 8.
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TGF-β/Smad signals are essential players in the differentiation of myofibroblast and interstitial deposition of ECM proteins after MI. Multiple pro-fibrotic molecules are involved in the pathogenesis of cardiac fibrosis. Thus, understanding molecular mechanisms underlying cardiac fibrosis is of great importance to the treatment of patients at high risk of developing heart failure after MI.
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Indeed, adverse cardiac fibrosis is an important independent risk factor for heart failure and is the leading cause of death in MI patients 7. Although the replacement fibrotic remodeling at early stage protects the heart from ventricular rupture, adverse remodeling leads to ventricular wall stiffness, impaired cardiac compliance, and consequently decreased cardiac contraction and/or diastolic function 2, 4– 6. Mainly differentiated from fibroblasts, activated myofibroblasts secrete a large amount of extracellular matrix (ECM), such as fibronectin (FN) and collagen, to replace the lost heart tissue, leading to structural and molecular remodeling of the heart 2, 3. The elevated inflammatory cytokines and growth factors including transforming growth factor-β (TGF-β) then recruit and activate myofibroblasts. Thus, our results reveal a novel mechanism underlying cardiac fibrosis following myocardial infarction, and provide a therapeutic strategy for cardiac remodeling related heart diseases.įollowing myocardial infarction (MI), inflammatory cells such as neutrophils and macrophages recruit to the injured area to clear cardiomyocyte debris and secrete inflammatory cytokines 1. Inhibition or knockdown of Sec61α blocked Nogo-C-induced increase of cytosolic Ca 2+ concentration and inhibited Nogo-C- and TGF-β1-induced fibrotic responses in cardiac fibroblasts, suggesting that Nogo-C regulates cardiac fibrosis through interacting with Sec61α to mediate the Ca 2+ leakage from endoplasmic reticulum. Nogo-C interacted with Sec61α on endoplasmic reticulum and stabilized Sec61α protein by inhibiting its ubiquitination. Moreover, overexpression of Nogo-C caused increased Sec61α, the Ca 2+ leakage channel on endoplasmic reticulum membrane. Mechanistically, we found that Nogo-C increased intracellular Ca 2+ concentration and buffering Ca 2+ totally abolished Nogo-C-induced fibrotic responses. Functionally, Nogo-C deficiency suppressed pro-fibrogenic proteins in post-myocardial infarction hearts and ameliorated post-myocardial infarction cardiac function. Overexpression of Nogo-C in cardiac fibroblasts increased expression of pro-fibrogenic proteins, while knockdown of Nogo-C inhibited the fibrotic responses of cardiac fibroblasts to Ang II- or TGF-β1 stimulation. In the present study, we found that Nogo-C was upregulated in fibrotic hearts after myocardial infarction and in Ang II- or TGF-β1-stimulated cardiac fibroblasts. Our previous study found that Nogo-C regulated cardiomyocyte apoptosis during myocardial infarction. Nogo-C protein ubiquitously expresses in tissues including in the heart. However, molecular mechanisms associated with the pathogenesis of cardiac fibrosis following myocardial infarction are not yet fully understood.
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Cardiac fibrosis is an independent risk factor for heart failure and even the leading cause of death in myocardial infarction patients.