Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling

Alpha-lipoic acid (alpha -LA), a well-known antioxidant, was proved to active ALDH2 in nitrate tolerance and diabetic animal model. However, the therapeutic advantage of alpha -LA for heart failure and related signaling pathway have not been explored. This study was designed to examine the role of alpha -LA-ALDH2 in heart failure injury and mitochondrial damage. ALDH2 knockout (ALDH2(-/-)) mice and primary neonatal rat cardiomyocytes (NRCMs) were subjected to assessment of myocardial function and mitochondrial autophagy. Our data demonstrated alpha -LA significantly reduced the degree of TAC-induced LV hypertrophy and dysfunction in wild-type mice, not in ALDH2(-/-) mice. In molecular level, alpha -LA significantly restored ALDH2 activity and expression as well as increased the expression of a novel mitophagy receptor protein FUNDC1 in wild-type TAC mice. Besides, we confirmed that ALDH2 which was activated by alpha -LA governed the activation of Nrf1-FUNDC1 cascade. Our data suggest that alpha -LA played a positive role in protecting the heart against adverse effects of chronic pressure overload.