Abstract
Cardiac fibrosis is an independent risk factor for heart failure and even the leading cause of death in myocardial infarction patients. However, molecular mechanisms associated with the pathogenesis of cardiac fibrosis following myocardial infarction are not yet fully understood. Nogo-C protein ubiquitously expresses in tissues including in the heart. Our previous study found that Nogo-C regulated cardiomyocyte apoptosis during myocardial infarction. 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. 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. Functionally, Nogo-C deficiency suppressed pro-fibrogenic proteins in post-myocardial infarction hearts and ameliorated post-myocardial infarction cardiac function. Mechanistically, we found that Nogo-C increased intracellular Ca2+ concentration and buffering Ca2+ totally abolished Nogo-C-induced fibrotic responses. Moreover, overexpression of Nogo-C caused increased Sec61α, the Ca2+ leakage channel on endoplasmic reticulum membrane. Nogo-C interacted with Sec61α on endoplasmic reticulum and stabilized Sec61α protein by inhibiting its ubiquitination. Inhibition or knockdown of Sec61α blocked Nogo-C-induced increase of cytosolic Ca2+ 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 Ca2+ leakage from endoplasmic reticulum. Thus, our results reveal a novel mechanism underlying cardiac fibrosis following myocardial infarction, and provide a therapeutic strategy for cardiac remodeling related heart diseases.
Highlights
Following myocardial infarction (MI), inflammatory cells such as neutrophils and macrophages recruit to the injured area to clear cardiomyocyte debris and secrete inflammatory cytokines[1]
We found that Neurite outgrowth inhibitor proteins (Nogo)-C was elevated in post-MI cardiac fibrotic tissue, whereas Nogo-C deficiency ameliorated cardiac fibrosis and improved cardiac function
After MI, cardiac fibroblasts play multifaceted roles including the activation of inflammatory reaction, paracrine signaling, and scar formation
Summary
Following myocardial infarction (MI), inflammatory cells such as neutrophils and macrophages recruit to the injured area to clear cardiomyocyte debris and secrete inflammatory cytokines[1]. TGF-β/Smad signals are essential players in the differentiation of myofibroblast and interstitial deposition of ECM proteins after MI. TGF-β-mediated production of ECM in cardiac fibroblasts is Smad3-dependent[5,8]. Smad[3] regulates the promoter activity of connective tissue growth factor (CTGF), a key mediator of ECM production during cardiac fibrotic remodeling[9]. Smad-independent signals such as p38 mitogen-activated protein kinase (MAPK) have been associated with the profibrotic TGF-β response[10]. In addition to TGF-β, renin-angiotensin system plays an important role in the cardiac remodeling. Activated myofibroblasts express angiotensin II (Ang II), the central part of the renin-angiotensin system, and elevated Ang II regulates the differentiation of myofibroblasts or the expression of ECM proteins. Similar studies found that reducing the cytoplasm Ca2+ by the inhibition of T/L-type calcium channel, N-type calcium channel, or Orai[1] storeoperated calcium entry, inhibits fibrosis[12,13,14,15], raising the prospect for pharmacologic intervention of cardiac fibrosis by inhibiting Ca2+ signals
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