AMPKα2 deficiency exacerbates hypoxia-induced pulmonary hypertension by promoting pulmonary arterial smooth muscle cell proliferation

Increased evidence indicates that adenosine monophosphate-activated protein kinase (AMPK) plays a vital role in vascular homeostasis, especially under hypoxia, and protects against the progression of pulmonary hypertension (PH). However, the role of AMPK in the pathogenesis of PH remains to be clarified. In the present study, we confirmed that a loss of AMPK alpha 2 exacerbated the development of PH by using hypoxia-induced PH model in AMPK alpha 2(-/-)mice. After a 4-week period of hypoxic exposure, AMPK alpha 2(-/-)mice exhibited more severe pulmonary vascular remodeling and pulmonary vascular smooth muscle cell (SMC) proliferation when compared with wild type (WT) mice. In vitro, AMPK alpha 2 knockdown promoted the proliferation of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia. This phenomenon was accompanied by upregulated Skp2 and downregulated p27(kip1)expression and was abolished by rapamycin, an inhibitor of mTOR. These results indicate that AMPK alpha 2 deficiency exacerbates hypoxia-induced PH by promoting PASMC proliferation via the mTOR/Skp2/p27(kip1)signaling axis. Therefore, enhanced AMPK alpha 2 activity might underlie a novel therapeutic strategy for the management of PH.