Activation of activator protein 2 alpha by aspirin alleviates atherosclerotic plaque growth and instability in vivo

// Jing-Jing Yang 1 , Peng Li 2 , Fu Wang 1 , Wen-Jing Liang 1 , Hui Ma 1 , Yuan Chen 1 , Zhi-Min Ma 3 , Quan-Zhong Li 4 , Qi-Sheng Peng 5 , Yun Zhang 1 and Shuang-Xi Wang 1,2 1 Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, School of Medicine, Shandong University, Jinan, China 2 Department of Pharmacology, College of Pharmacy, Xinxiang Medical University, Xinxiang, China 3 Division of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China 4 Division of Cardiology, The Affiliated Hospital, Guilin Medical University, Guilin, China 5 Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, China Correspondence to: Shuang-Xi Wang, email: // Yun Zhang, email: // Keywords : activator protein 2α, aspirin, IkBα, atherosclerosis, Pathology Section Received : March 24, 2016 Accepted : June 17, 2016 Published : July 04, 2016 Abstract Aims: Aspirin has been used for the secondary prevention and treatment of cardiovascular disease for several decades. We investigated the roles of transcriptional factor activator protein 2α (AP-2α) in the beneficial effects of aspirin in the growth and vulnerability of atherosclerotic plaque. Methods and Results: In mice deficient of apolipoprotein E ( Apoe -/- ), aspirin (20, 50 mg/kg/day) suppressed the progression of atherosclerosis in aortic roots and increased the plaque stability in carotid atherosclerotic plaques induced by collar-placement. In vivo lentivirus-mediated RNA interference of AP-2α reversed the inhibitory effects of aspirin on atherosclerosis in Apoe -/- mice. Mechanically, aspirin increased AP-2α phosphorylation and its activity , upregulated IkBα mRNA and protein levels, and reduced oxidative stress in cultured vascular smooth muscle cells . Furthermore, deficiency of AP-2α completely abolished aspirin-induced upregulation of IkBα levels and inhibition of oxidative stress in Apoe -/- mice. Clinically, conventional doses of aspirin increased AP-2α phosphorylation and IkBα protein expression in humans subjects. Conclusion: Aspirin activates AP-2α to upregulate IkBα gene expression, resulting in attenuations of plaque development and instability in atherosclerosis.