Abstract
Alpha-lipoic acid (α-LA), a well-known antioxidant, was proved to active ALDH2 in nitrate tolerance and diabetic animal model. However, the therapeutic advantage of α-LA for heart failure and related signaling pathway have not been explored. This study was designed to examine the role of α-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 α-LA significantly reduced the degree of TAC-induced LV hypertrophy and dysfunction in wild-type mice, not in ALDH2−/− mice. In molecular level, α-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 α-LA governed the activation of Nrf1–FUNDC1 cascade. Our data suggest that α-LA played a positive role in protecting the heart against adverse effects of chronic pressure overload.
Highlights
Heart failure is linked with high mobility and mortality rate worldwide
The quantitative real-time polymerase chain reaction (PCR) results showed that α-LA reduced these hypertrophic pathological phenotypes were accompanied by the downregulation of hypertrophic genes, including atrial natriuretic polypeptide (ANP), brain natriuretic peptide (BNP), myosin heavy chain beta (β-Mhc), and fibrotic genes including connective tissue growth factor (Ctgf), collagen1a1 (Col1a1), and collagen3a1 (Col3a1) (Supplementary Fig. S1B)
In the present study, we showed that alpha-lipoic acid therapy attenuated pressure overload-induced cardiac hypertrophy and remodeling and improved the cardiac function in transverse aortic constriction (TAC) mice via Acetaldehyde dehydrogenase 2 (ALDH2)-dependent manner
Summary
Heart failure is linked with high mobility and mortality rate worldwide. Structural cardiac remodeling, which includes myocardial hypertrophy and fibrosis, has been demonstrated to contribute significantly to ventricular dysfunction in heart failure[1]. Understanding the role of mitochondrial metabolism in the development of heart failure is helpful for early detection of risk factors and for the application of effective therapeutic options aiming to improve the prognosis of heart failure. ALDH2 has three enzyme activities, including dehydrogenase, esterase, and reductase, and the most studied activity is the dehydrogenase activity, which can remove excess aldehyde metabolites. Our previous studies have defined its important cardio-protective role in the setting of various risk factors of heart failure, such as coronary artery disease (CAD), hypertension, diabetes, alcoholism, and other susceptibilities[5,6,7,8]. The indispensable role of ALDH2 in the pathogenesis of heart failure reveals that targeting ALDH2 might be a potential therapeutic option for heart failure and other cardiovascular diseases. Many studies are performed to explore the efficacy of drugs capable of activating ALDH2, such as Alda-1, clinical promotion is limited due to cytotoxicity or other reasons of applied drugs[9]
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