Nogo-C regulates post myocardial infarction fibrosis through the interaction with ER Ca2+ leakage channel Sec61α in mouse hearts

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 pro...

Full description

Saved in:
Bibliographic Details
Published in:Cell death & disease 2018-05, Vol.9 (6), p.1-15, Article 612
Main Authors: Weng, Lin, Jia, Shi, Xu, Chunling, Ye, Jingjing, Cao, Yangpo, Liu, Yingying, Zheng, Ming
Format: Article
Language:English
Subjects:
Angiotensin II
Apoptosis
C protein
Calcium (intracellular)
Calcium (reticular)
Calcium buffering
Cardiomyocytes
Coronary artery disease
Endoplasmic reticulum
Fibroblasts
Fibrosis
Heart attacks
Heart diseases
Leakage
Molecular modelling
Myocardial infarction
Nogo protein
Transforming growth factor-b1
Ubiquitination
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 Ca 2+ concentration and buffering Ca 2+ totally abolished Nogo-C-induced fibrotic responses. Moreover, overexpression of Nogo-C caused increased Sec61α, the Ca 2+ 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 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. Thus, our results reveal a novel mechanism underlying cardiac fibrosis following myocardial infarction, and provide a therapeutic strategy for cardiac remodeling related heart diseases.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-018-0598-6