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

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

  • Biochim Biophys Acta Mol Basis Dis. 2025 Aug;1871(6):167863. doi: 10.1016/j.bbadis.2025.167863.
Zhengyu Sun 1,  Wendi Jiang 2,  Guoqing Lu 1,  Yangyang Ding 1,  Lei Wang 1,  Jiayi Geng 3,  Ningning Zhang 1,  Hongju Wang 4,  Pinfang Kang 5,  Bi Tang 6
Affiliations

Affiliations

  • 1 Department of Cardiovascular Medicine, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233000, PR China; Key Laboratory of Basic and Clinical Cardiovascular and Cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui Province 233004, PR China.
  • 2 Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University, Bengbu, Anhui 233000, PR China; Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Bengbu, Anhui 233000, PR China.
  • 3 Department of Physiology, Bengbu Medical University, Bengbu, Anhui 233000, PR China.
  • 4 Department of Cardiovascular Medicine, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233000, PR China.
  • 5 Department of Cardiovascular Medicine, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233000, PR China; Key Laboratory of Basic and Clinical Cardiovascular and Cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui Province 233004, PR China. Electronic address: kangpinfang.1016@163.com.
  • 6 Department of Cardiovascular Medicine, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233000, PR China. Electronic address: bitang2000@163.com.
PMID: 40274079 DOI: 10.1016/j.bbadis.2025.167863
Abstract

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 p16INK4a, 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, p16INK4a, 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-p16INK4a signaling pathway in HPH, providing a novel target for PAH treatment.

Keywords

4-HNE/ERK1/2-p16(INK4a) signaling pathway; ALDH2; Cell proliferation; Cellular senescence; PAH; PASMC.

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