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Nogo-C regulates post myocardial infarction fibrosis through the interaction with ER Ca2+ leakage channel Sec61α in mouse hearts
- Source :
- Cell Death and Disease, Vol 9, Iss 6, Pp 1-15 (2018), Cell Death & Disease
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group, 2018.
-
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.
- Subjects :
- 0301 basic medicine
Cardiac function curve
Cancer Research
medicine.medical_specialty
Cardiac fibrosis
Nogo Proteins
Immunology
Myocardial Infarction
Infarction
030204 cardiovascular system & hematology
Endoplasmic Reticulum
Models, Biological
Article
Transforming Growth Factor beta1
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Fibrosis
Internal medicine
mental disorders
Medicine
Animals
Myocardial infarction
Calcium Signaling
lcsh:QH573-671
Mice, Knockout
Endoplasmic reticulum membrane
business.industry
lcsh:Cytology
Endoplasmic reticulum
Angiotensin II
Myocardium
Cell Biology
Fibroblasts
medicine.disease
Rats
Up-Regulation
030104 developmental biology
Endocrinology
Heart failure
Heart Function Tests
cardiovascular system
Calcium
business
SEC Translocation Channels
psychological phenomena and processes
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 9
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Cell Death and Disease
- Accession number :
- edsair.doi.dedup.....e12f5e29fa795e0dc4d3667fc75a2a5d