Aldehyde Dehydrogenase-2 Attenuates Myocardial Remodeling and Contractile Dysfunction Induced by a High-Fat Diet

Abstract

Background/Aims: Consumption of a high-fat (HF) diet exacerbates metabolic cardiomyopathy through lipotoxic mechanisms. In this study, we explored the role of aldehyde dehydrogenase-2 (ALDH2) in myocardial damage induced by a HF diet. Methods: Wild-type C57 BL/6J mice were fed a HF diet or control diet for 16 weeks. ALDH2 overexpression was achieved by injecting a lentiviral ALDH2 expression vector into the left ventricle. Results: Consumption of a HF diet induced metabolic syndrome and myocardial remodeling, and these deleterious effects were attenuated by ALDH2 overexpression. In addition, ALDH2 overexpression attenuated the cellular apoptosis and insulin resistance associated with a HF diet. Mechanistically, ALDH2 overexpression inhibited the expression of c-Jun N-terminal kinase (JNK)-1, activated protein 1 (AP-1), insulin receptor substrate 1 (IRS-1), 4- hydroxynonenal, caspase 3, transforming growth factor β1, and collagen I and III, and enhanced Akt phosphorylation. Conclusion: ALDH2 may effectively attenuate myocardial remodeling and contractile defects induced by a HF diet through the regulation of the JNK/AP-1 and IRS-1/Akt signaling pathways. Our study demonstrates that ALDH2 plays an essential role in protecting cardiac function from lipotoxic cardiomyopathy.

Aldehyde Dehydrogenase 2 (ALDH2) Deficiency, Obesity, and Atrial Fibrillation Susceptibility: Unraveling the Connection

“…Studies, such as Mali et al's investigation in mice with metabolic syndrome induced by an HFD, highlight the role of decreased myocardial ALDH2 activity due to 4-HNE adduct formation in contributing to cardiac hypertrophy [29]. In a different approach, Li et al demonstrated that overexpression of ALDH2 effectively attenuated myocardial remodeling and contractile defects induced by an HFD through the regulation of JNK/AP-1 and IRS-1/Akt signaling pathways [30]. The protective effect of ALDH2 against cardiac remodeling in HFD-induced obesity was further affirmed by Wang et al, who utilized an ALDH2 transgenic mice model [31].…”

Metabolic Remodeling and Implicated Calcium and Signal Transduction Pathways in the Pathogenesis of Heart Failure

“…A previous work showed complex formation between ETC complex III and phosphorylated JNK and P38 [ 181 ]. Others have shown that overexpression of mt-aldehyde dehydrogenase 2 or AMPK is protective in the heart and endothelial cells, respectively, through the reciprocal attenuation of JNK activity and preservation of mt-function and biogenesis [ 183 , 184 ].…”