Activation of AMP-activated protein kinase ablated the formation of aortic dissection by suppressing vascular inflammation and phenotypic switching of vascular smooth muscle cells

Aortic dissection (AD) is a fatal vascular disease in absence of effective pharmaceutical therapy. Adenosine monophosphate-activated protein kinase α (AMPKα) plays a critical role in various cardiovascular diseases. Whether AMPKα is involved in the pathogenesis of aortic dissection remains unknown. We aimed to determine whether activation of AMPKα prevents the formation of AD.Reduced expression of phosphorylated AMPKα (Thr172) and exacerbated phenotypic switching were observed in human aortic tissues from aortic dissection patients compared with those in tissues from controls. In vivo, the formation of aortic dissection in ApoE-/- mice was successfully induced by continuous infusion of angiotensin II (AngII) for two weeks, characterized by the activation of vascular inflammation, infiltration of macrophages and phenotypic switching of vascular smooth muscle cells (VSMCs). rAAV2-mediated overexpression of constitutively active AMPKα (CA-AMPKα) enhanced the expression of phosphorylated AMPKα (Thr172) and attenuated AngII-induced occurrence of aortic dissection by suppressing the infiltration of macrophages, activation of vascular inflammation and phenotypic switching of VSMCs. The pathogenesis above was conversely exacerbated by rAAV2-mediated overexpression of dominant negative AMPKα2 (DN-AMPKα). In vitro, we demonstrated that the administration of an AMPK agonist (AICAR) or transfection of CA-AMPKα induced the activation of AMPKα and then ameliorated AngII-induced phenotypic switching in the VSMCs and inflammation in the bone marrow-derived macrophages (BMDMs). This could be reversed by the addition of AMPK inhibitor compound C or transfection of DN-AMPKα.Impaired activation of AMPKα may increase the susceptibility to aortic dissection. Our findings verified the protective effects of AMPKα on the formation of aortic dissection and may provide evidence for clinical prevention or treatment.