Pravastatin activates activator protein 2 alpha to augment the angiotensin II-induced abdominal aortic aneurysms.
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.
Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.|Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
Hui
H
Ma
Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.
Wen-Jing
WJ
Liang
Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.
Mei-Rong
MR
Shan
Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.
Xue-Qing
XQ
Wang
Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.
Sheng-Nan
SN
Zhou
Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.
Yuan
Y
Chen
Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.
Tao
T
Guo
College of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
Peng
P
Li
Department of Neurology, The People's Hospital of Xishui County, Huangang, Hubei, China.
Hai-Ya
HY
Yu
Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China.
Chao
C
Liu
College of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
Ya-Ling
YL
Yin
Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
Yu-Lin
YL
Wang
Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
Bo
B
Dong
Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.
Xin-Yan
XY
Pang
Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.|College of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
Shuang-Xi
SX
Wang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017035:Pravastatin / Q000009:adverse effects*; D015398:Signal Transduction; D050656:Transcription Factor AP-2 / Q000378:metabolism*
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D050656:Transcription Factor AP-2; D000804:Angiotensin II; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; D017035:Pravastatin
AMP-activated protein kinase; Pathology Section; abdominal aortic aneurysm; activator protein 2 alpha; matrix metalloproteinase 2; pravastatin