Matricellular Protein Cilp1 Promotes Myocardial Fibrosis in Response to Myocardial Infarction.
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ABSTRACT:
SUBMITTER: Zhang QJ
PROVIDER: S-EPMC8722455 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
Publications
Matricellular Protein Cilp1 Promotes Myocardial Fibrosis in Response to Myocardial Infarction.
Zhang Qing-Jun QJ He Yu Y Li Yongnan Y Shen Huali H Lin Ling L Zhu Min M Wang Zhaoning Z Luo Xiang X Hill Joseph A JA Cao Dian D Luo Richard L RL Zou Raymond R McAnally John J Liao Jun J Bajona Pietro P Zang Qun S QS Yu Yonghao Y Liu Zhi-Ping ZP
Circulation research 20211006 11
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Project description:Myocardial infarction (MI) is a leading cause of maladaptive cardiac remodeling and heart failure. In the damaged heart, loss of function is mainly due to cardiomyocyte death and remodeling of the cardiac tissue. The current study shows that A-kinase anchoring protein 2 (AKAP2) orchestrates cellular processes favoring cardioprotection in infarcted hearts. Induction of AKAP2 knockout (KO) in cardiomyocytes of adult mice increases infarct size and exacerbates cardiac dysfunction after MI, as visualized by increased left ventricular dilation and reduced fractional shortening and ejection fraction. In cardiomyocytes, AKAP2 forms a signaling complex with PKA and the steroid receptor co-activator 3 (Src3). Upon activation of cAMP signaling, the AKAP2/PKA/Src3 complex favors PKA-mediated phosphorylation and activation of estrogen receptor α (ERα). This results in the upregulation of ER-dependent genes involved in protection against apoptosis and angiogenesis, including Bcl2 and the vascular endothelial growth factor a (VEGFa). In line with these findings, cardiomyocyte-specific AKAP2 KO reduces Bcl2 and VEGFa expression, increases myocardial apoptosis and impairs the formation of new blood vessels in infarcted hearts. Collectively, our findings suggest that AKAP2 organizes a transcriptional complex that mediates pro-angiogenic and anti-apoptotic responses that protect infarcted hearts.
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