Aldehyde dehydrogenase 2 deficiency blunts compensatory cardiac hypertrophy through modulating Akt phosphorylation early after transverse aorta constriction in mice

Abstract

AimsThis study was designed to examine the impact of mitochondrial aldehyde dehydrogenase 2 (ALDH2) on transverse aorta constriction (TAC)-induced cardiac hypertrophy and related molecular mechanisms using an ALDH2 knockout (ALDH2−/−) murine model. MethodsMale wild-type and ALDH2−/− mice were subjected to TAC or sham operation (n=6–8 for each group). After two weeks, cardiac function was assessed by echocardiography and hemodynamic measurements. Myocardial phosphorylated and total PI3K, the catalytic subunit of PI3Ks (p110α and p110γ), Akt, and total PTEN levels were detected by Western blotting. Cardiomyocytes were stretched for 6h in vitro in the presence or absence of Alda-1 (a small-molecule activator of ALDH2) prior to assessment of phosphorylated PI3K, Akt and total PTEN expressions by Western blot. ResultsHeart to body weight ratio and left ventricular posterior wall thickness as well as the cross-sectional area of cardiomyocyte were significantly lower in ALDH2−/− mice than in wild-type mice following TAC. Western blot analysis showed p110γ was upregulated post TAC in both wild-type mice and ALDH2−/− mice, phosphorylation of Akt was disrupted, PTEN expression was upregulated in ALDH2−/− mice post TAC while phosphorylated PI3K, p110α and p110γ expression was similar between ALDH2−/− and wild-type mice post TAC. In vitro, phosphorylation of Akt was significantly accentuated and PTEN expression was reduced while PI3K phosphorylation remained unchanged in stretched cardiomyocytes pretreated by Alda-1 compared to stretched cardiomyocytes treated by saline. ConclusionsOur results show that ALDH2 deficiency attenuates compensatory cardiac hypertrophy through regulating Akt but not PI3K phosphorylation early after TAC in mice.