Background: Aortic dissection (AD) is a fatal vascular disease in absence of effective pharmaceutical therapy. Adenosine monophosphate-activated protein kinase alpha (AMPK alpha) plays a critical role in various cardiovascular diseases. Whether AMPK alpha is involved in the pathogenesis of aortic dissection remains unknown. We aimed to determine whether activation of AMPK alpha prevents the formation of AD. Methods and results: Reduced expression of phosphorylated AMPK alpha (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 AMPK alpha (CA-AMPK alpha) enhanced the expression of phosphorylated AMPK alpha (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 AMPK alpha 2 (DN-AMPK alpha). In vitro, we demonstrated that the administration of an AMPK agonist (AICAR) or transfection of CA-AMPK alpha induced the activation of AMPK alpha 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-AMPK alpha. Conclusion: Impaired activation of AMPK alpha may increase the susceptibility to aortic dissection. Our findings verified the protective effects of AMPK alpha on the formation of aortic dissection and may provide evidence for clinical prevention or treatment.