[Activation of ALDH2 alleviates hypoxic pulmonary hypertension in mice by upregulating the SIRT1/PGC-1α signaling pathway].

Objective: To investigate whether activation of mitochondrial acetal dehydrogenase 2 (ALDH2) alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.

Methods: Thirty 8-week-old C57 BL/6 mice were randomized into control, hypoxia, and hypoxia +Alda-1 (an ALDH2 activator) group (n=10), and the mice in the latter two groups, along with 10 ALDH2 knockout (ALDH2^-/-) mice, were exposed to hypoxia (10% O₂, 90% N₂) with or without daily intraperitoneal injection of Alda-1 for 4 weeks. The changes in right ventricular function and pressure (RVSP) of the mice were evaluated by echocardiography and right ventricular catheter test, and pulmonary artery pressure was estimated based on RVSP. Pulmonary vascular remodeling, right ventricular injury, myocardial α -SMA expression, distal pulmonary arteriole muscle normalization, right ventricular cross-sectional area, myocardial cell hypertrophy, and right cardiac hypertrophy index were assessed with HE staining, immunofluorescence staining and WGA staining, and the expressions of ALDH2, SIRT1, PGC-1α, P16INK4A and P21^CIP1 were detected. In pulmonary artery smooth muscle cells with hypoxic exposure, the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.

Results: The wild-type mice with hypoxic exposure showed significantly increased RVSP, right ventricular free wall thickness and myocardial expressions of P16^INK4A and P21^CIP1, which were effectively lowered by treatment with Alda-1 but further increased in ALDH2^-/- mice. In cultured pulmonary artery smooth muscle cells, hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16^INK4A and P21^CIP1, which were all lowered by treatment with Alda-1, but its effect was obviously attenuated by EX527 treatment.

Conclusion: ALDH2 alleviates hypoxiainduced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.