Loss of ALDH2 accelerates the progression of pulmonary arterial hypertension through the 4-HNE/ERK1/2-p16INK4a signaling pathway

Senescence is an important causative factor in the development of pulmonary arterial hypertension (PAH). Aldehyde dehydrogenase 2 (ALDH2), an enzyme involved in aldehyde detoxification, plays a role in cardiovascular diseases associated with aldehyde accumulation. This study aimed to investigate the role of ALDH2 in hypoxia-induced pulmonary arterial smooth muscle cells (PASMCs) and PAH. ALDH2 knockout (ALDH2^−/−) mice and wild-type (WT) mice were exposed to a hypoxic environment with 10 ± 0.5 % oxygen concentration for 4 weeks to develop a chronic hypoxia-induced PAH (HPH) mouse model. We found that right ventricular hypertrophy and pulmonary arteriole muscularization were more severe in ALDH2^−/− mice compared to WT mice. Additionally, ALDH2^−/− mice exhibited elevated expression levels of 4-HNE, p-ERK1/2, the senescence-related protein p16^INK4a, and the senescence-associated secretory phenotype (SASP) compared to WT mice. Similarly, treatment with the ALDH2 inhibitor (Daidzin) significantly increased 4-HNE, p-ERK1/2, p16^INK4a, and SASP levels in PASMCs under hypoxia. Conversely, overexpression of ALDH2 reduced 4-HNE, p-ERK1/2, and PASMC senescence. Furthermore, exogenous 4-HNE, used to simulate hypoxia conditions, activated the ERK signaling pathway and induced PASMC senescence. However, ERK-specific inhibitors (PD98059) blocked hypoxia-induced PASMC senescence. These results demonstrate that ALDH2 deficiency induces PASMC senescence and promotes pulmonary vascular remodeling through the 4-HNE/ERK1/2-p16^INK4a signaling pathway in HPH, providing a novel target for PAH treatment.