Abstract 18812: Myocardial Senescence Induced by Inactivation Aldh2-SIRT1-GATA4 Pathway Involves in Heart Remolding After Acute Infarction
Introduction: It is well known that there exist myocardial apoptosis and necrosis after acute myocardial infarction (AMI). Moreover, our previous study has found cellular senescence occurs after cardiac hypoxia. Compared with cellular apoptosis and necrosis, senescent cells can secrete soluble factors continuously, termed as the senescence-associated secretory phenotype (SASP), by which to influence the local microenvironment.
Hypothesis: Myocardial senescence may play an important pathological role in the process of heart remolding after AMI, and the underlying mechanisms may be due to the accumulation of GATA4 resulted from ALDH2 inactivation-inhibited autophagy.
Methods: Myocardial senescence in myocardium after AMI was assessed by immunohistochemistry (p16Ink4a, p21CDKN1A and p53) and senescence- associated β-galactosidase (SA-β-gal) staining. And the abundance of mRNA relevant with SASP was quantified by RT-qPCR. To identify the molecular targets regulating cellular senescence, siRNAs were used to delete the core signaling proteins p53, p21 and p16 as well as GATA4 into neonatal rat myocardial cells. Then, the identified protein GATA4 was knocked down in C57BL/6 and ALDH2 KO mice by transfection of lentiviral vector. The markers of heart remolding and function were also evaluated after AMI.
Results: Aging-associated phenotypes were significantly increased in the infract region after AMI, where an accumulation of GATA4 was also detected. In vitro, although p53, p21, p16 and GATA4 all were involved in the cellular senescence, GATA4 contributed more significantly and mastered the release of SASP. And in vivo experiments showed that mice transfected with GATA4-shRNA lentiviral possessed improved heart remolding and function. We then found that the accumulation of GATA4 was due to the impaired autophagy after AMI, which can be reversed by ALDH2 or SIRT1 activator (alda-1 or resveratrol). ALDH2 was further verified as the upstream regulator of SIRT1-autophagy-GATA4 pathway by use of ALDH2 KO mice.
Conclusions: Our study identifies a new GATA4-dependnt regulatory mechanism governing myocardial aging and cardiac remodeling after AMI, which may be regulated by ALDH2 and SIRT1.
Author Disclosures: L. Xue: None. S. Cui: None. F. Yang: None. B. Liu: None. Q. Yuan: None. J. Pang: None. S. Wei: None. J. Wang: None. F. Xu: None. Y. Chen: None.
- © 2016 by American Heart Association, Inc.