Pravastatin activates activator protein 2 alpha to augment the angiotensin II-induced abdominal aortic aneurysms.

Hui Ma,Mei-Rong Shan,Shuang-Xi Wang,Bo Dong,Xue-Qing Wang,Yuan Chen,Wen-Jing Liang,Chao Liu,Hai-Ya Yu,Peng Li,Xin-Yan Pang,Tao Guo,Yu-Lin Wang,Sheng-Nan Zhou,Ya-Ling Yin

doi:10.18632/oncotarget.15104

Abstract

We have previously reported that activation of AMP-activated kinase alpha 2 (AMPKa2) 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 AMPKa2 and activator protein 2 alpha (AP-2a) 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-2a, and MMP2 in both basal and AngII-stressed conditions, which were abolished by tempol and compound C. Pravastatin-upregulated MMP2 was abrogated by AMPKa2 or AP-2a siRNA. Lentivirus-mediated gene silence of AMPKa2 or AP-2a abolished pravastatin-worsened AAA formations in AngII-infused Apoe−/− mice. Clinical investigations demonstrated that both AMPKa2 and AP-2a phosphorylations were increased in AAA patients or human subjects taking pravastatin. In conclusion, pravastatin promotes AAA formation through AMPKa2-dependent AP-2a activations.

Highlights

Abdominal aortic aneurysms (AAAs) are permanent dilations of the abdominal aorta with over 85% mortality after rupture
Histological analysis indicated that the maximal aortic diameter and the degradation of elastin were increased by pravastatin in Apoe−/− mice with AAA (Figure 1D-1F)
These results suggest that pravastatin promotes the angiotensin II (AngII)-induced AAA formation in Apoe-/mice

Summary

Introduction

Abdominal aortic aneurysms (AAAs) are permanent dilations of the abdominal aorta with over 85% mortality after rupture. AAA is characterized by dilatation of all layers of the arterial wall as a result of loss of elastin, vascular smooth muscle cell (VSMC) apoptosis, and compensatory collagen deposition [1,2,3]. Statins produce several adverse effects, such as insulin resistance [9], skeletal muscle toxicity and myocardial atrophy [10]. AMPK is activated by pravastatin in skeletal muscle and endothelial cells [11, 12]. We reported that AMPK www.impactjournals.com/oncotarget activation mediated AngII-induced AAA formation in Apoe-/- mice [13]. This alludes that pravastatin is potentially to promote AAA incidences

Objectives

Methods

Results

Conclusion