Research Papers: Pathology:
Pravastatin activates activator protein 2 alpha to augment the angiotensin II-induced abdominal aortic aneurysms
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Abstract
Hui Ma1,2, Wen-Jing Liang1, Mei-Rong Shan1, Xue-Qing Wang1, Sheng-Nan Zhou1, Yuan Chen1, Tao Guo1, Peng Li3, Hai-Ya Yu4, Chao Liu5, Ya-Ling Yin3, Yu-Lin Wang2, Bo Dong2, Xin-Yan Pang1 and Shuang-Xi Wang1,3
1 Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China
2 Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
3 College of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
4 Department of Neurology, The People’s Hospital of Xishui County, Huangang, Hubei, China
5 Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China
Correspondence to:
Shuang-Xi Wang, email:
Xin-Yan Pang, email:
Bo Dong, email:
Keywords: abdominal aortic aneurysm, pravastatin, AMP-activated protein kinase, activator protein 2 alpha, matrix metalloproteinase 2, Pathology Section
Received: September 09, 2016 Accepted: January 16, 2017 Published: February 04, 2017
Abstract
We have previously reported that activation of AMP-activated kinase alpha 2 (AMPKα2) by nicotine or angiotensin II (AngII) instigates formation of abdominal aortic aneurysms (AAA) in Apoe-/- mice. Statins, used to treat hyperlipidemia widely, activate AMPK in vascular cells. We sought to examine the effects of pravastatin on AAA formation and uncover the molecular mechanism. The AAA model was induced by AngII and evaluated by incidence, elastin degradation, and maximal abdominal aortic diameter in Apoe-/- mice. The phosphorylated levels of AMPKα2 and activator protein 2 alpha (AP-2α) were examined in cultured vascular smooth muscle cells (VSMCs) or in mice. We observed that pravastatin (50 mg/kg/day, 8 weeks) remarkably increased the AngII-induced AAA incidence in mice. In VSMCs, pravastatin increased the levels of pAMPK, pAP-2α, and MMP2 in both basal and AngII-stressed conditions, which were abolished by tempol and compound C. Pravastatin-upregulated MMP2 was abrogated by AMPKα2 or AP-2α siRNA. Lentivirus-mediated gene silence of AMPKα2 or AP-2α abolished pravastatin-worsened AAA formations in AngII-infused Apoe-/- mice. Clinical investigations demonstrated that both AMPKα2 and AP-2α phosphorylations were increased in AAA patients or human subjects taking pravastatin. In conclusion, pravastatin promotes AAA formation through AMPKα2-dependent AP-2α activations.
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