Alpha-Lipoic Acid Protects Against Pressure Overload-induced Heart Failure <i>via</i> ALDH2-Dependent Nrf1-FUNDC1 Signaling

Abstract

Background: Acetaldehyde dehydrogenase 2 (ALDH2) could protect the heart against pressure overload-induced heart failure in mice. Alpha-lipoic acid (α-LA), a well-known antioxidant, was capable of activating ALDH2. However, impact of α-LA on pressure overload-induced heart failure remains unknown now. Methods: α-LA on pressure overload-induced heart failure were assessed using ALDH2 knockout (ALDH2-/-) mice and primary neonatal rat cardiomyocytes (NRCMs). TAC-induced left ventricular hypertrophy and contractile function were assessed by echocardiography and cell shortening/relengthening system. Heart histological measurement were using H&E, WGA, Masson’s trichrome, DHE and TUNEL. Mitochondrial mass and morphology were visualized using TEM. The target proteins and their interactions was investigated by bioinformatic analysis, luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Findings: In vivo, we found that supplement of α-LA significantly reduced transverse aortic constriction (TAC)-induced LV hypertrophy and dysfunction in wild-type mice, as evidenced by preserved LV ejection fraction, a more favorable histologic change and restoration of mitochondrial normality. Whereas, α-LA did not affect TAC induced LV hypertrophy and dysfunction in ALDH2 gene knockout (KO) mice. In molecular level, α-LA significantly restored ALDH2 activity and expression as well as upregulated the expression of FUN14 domain containing 1 (FUNDC1), an activator of hypoxia-induced mitophagy, in wild type TAC mice, again, these effects were not observed in ALDH2 gene KO mice undergoing TAC. In angiotensin II –induced hypertrophy in vitro model of neonatal rat cardiomyocytes (NRCMs), we confirmed that α-LA could activate ALDH2 and nuclear respiratory factor 1 (Nrf1) - FUNDC-1 cascade. Interpretation: These data supported the notion that α-LA treatment could protect the heart against adverse effects of chronic pressure overload via ALDH2-dependent Nrf1-FUNDC1 signaling pathway. Funding Statement: This work was supported by the National Science Fund for Distinguished Young Scholars to AS (81725002) and a grant of Innovative Research Groups of the National Natural Science Foundation of China (81521001). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: All of the mice experiments were performed under protocols approved by the Institutional Animal Care and Use Committee of the Fudan University.