Abstract: AIM:To investigate the role of ALDH2 in autophagy and cell survival in cardiomyocytes exposed to high glucose (HG). METHODS: H9c2 myocytes were cultured in DMEM with normal (5.5 mmol/L) or high doses (33 mmol/L) of glucose for 72 h in absence or presence of ALDH2 agonist Alda-1 (20 μmol/L) and autophagy inhibitor 3-methyladenine (3-MA) (10 mmol/L). The expression of ALDH2, autophagy gene-related protein 5 (ATG5), and microtubule-associated protein 1 light chain 3 (LC3) were analyzed by Western blot. The number of autophagosomes was measured by immunofluorescence, cell viability was detected by CCK-8 assay and the apoptotic index was examined by TUNEL. RESULTS: Compared with control group, HG induced decreased protein expression of ALDH2, ATG5 and LC3II, significantly reduced cell viability and increased the cell apoptosis index. Alda-1 upregulated the expression of ALDH2, ATG5 and LC3II and autophagosome cultured with high glucose, enhanced the cell viability and reduced the apoptosis index, which were reversed by 3-MA. CONCLUSION: ALDH2 increases cell viability and downregulates the apoptosis index in cardiomyocytes exposed to high glucose by autophagy.