Aldehyde dehydrogenase 2 activation in aged heart improves the autophagy by reducing the carbonyl modification on SIRT1

Abstract

Cardiac aging is characterized by accumulation of damaged proteins and decline of autophagic efficiency. Here, by forestalling SIRT1 carbonylated inactivation in aged heart, we determined the benefits of activation of aldehyde dehydrogenase 2 (ALDH2) on the autophagy. In this study, the ALDH2 KO mice progressively developed age-related heart dysfunction and showed reduction in the life span, which strongly suggests that ALDH2 ablation leads to cardiac aging. What's more, aged hearts displayed a significant decrease ALDH2 activity, resulting in accumulation of 4-HNE-protein adducts and protein carbonyls, impairment in the autophagy flux, and, consequently, deteriorated cardiac function after starvation. Sustained Alda-1 (selective ALDH2 activator) treatment increased cardiac ALDH2 activity and abrogated these effects. Using SIRT1 deficient heterozygous (Sirt1+/−) mice, we found that SIRT1 was necessary for ALDH2 activation-induced autophagy. We further demonstrated that ALDH2 activation attenuated SIRT1 carbonylation and improved SIRT1 activity, thereby increasing the deacetylation of nuclear LC3 and FoxO1. Sequentially, ALDH2 enhanced SIRT1 regulates LC3-Atg7 interaction and FoxO1 increased Rab7 expression, which were both necessary and sufficient for restoring autophagy flux. These results highlight that both accumulation of proteotoxic carbonyl stress linkage with autophagy decline contribute to heart senescence. ALDH2 activation is adequate to improve the autophagy flux by reducing the carbonyl modification on SIRT1, which in turn plays an important role in maintaining cardiac health during aging.

Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA4‐Dependent CCN1 Secretion

“…The present investigation is a continuation and extension of our earlier work that provided primary evidence on the activated senescence‐associated phenotype after AMI 26. In this study, we determined that myocardial senescence is involved in multiple rodent heart diseases and human ischemic heart tissues.…”

“…We have a longstanding interest in the effects of ALDH2 and the cardiovascular system 24, 25, 26. We previously found that ALDH2 activation by Alda‐1 reduced the senescence phenotype in H9C2 cell lines 23.…”

The Prognostic Role of SIRT1-Autophagy Axis in Gastric Cancer

“…Many studies have shown that SIRT1 has a close relationship with autophagy in several physiological and pathological processes [23, 33, 34]. The role of SIRT1 in tumors is significantly heterogeneous.…”

Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque

“…Recently, our studies further indicated that the ALDH2 mutation is tied with levels of high-sensitivity C-reactive protein, a classical inflammatory biomarker, and the number of circulating endothelial progenitor cells [15]. In addition, previous studies showed that overexpression of ALDH2 attenuates myocardial apoptosis [16] and ALDH2 plays an important role in myocardial protection [17–19]. It is well conceived that lipids, endothelial dysfunction or injury-repair imbalance, and inflammation play critical roles in atherosclerosis progression and atherosclerotic plaque vulnerability, which are recognized as a pivotal mechanism of ACS [20].…”