title: AMP-Activated Protein Kinase Alpha 2 Deletion Induces VSMC Phenotypic Switching and Reduces Features of Atherosclerotic Plaque Stability.
abstract: BACKGROUND
  AMP-activated protein kinase (AMPK) has been reported to play a protective role in atherosclerosis. However, whether AMPKα2 controls atherosclerotic plaque stability remains unknown.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the impact of AMPKα2 deletion on atherosclerotic plaque stability in advanced atherosclerosis at the brachiocephalic arteries and to elucidate the underlying mechanisms.
  
  
  RESULTS
  Features of atherosclerotic plaque stability and the markers for contractile or synthetic vascular smooth muscle cell (VSMC) phenotypes were monitored in the brachiocephalic arteries from Apoe(-/-)AMPKα2(-/-) mice or VSMC-specific AMPKα2(-/-) mice in an Apoe(-/-) background (Apoe(-/-)AMPKα2(sm-/-)) fed Western diet for 10 weeks. We identified that Apoe(-/-)AMPKα2(-/-) mice and Apoe(-/-)AMPKα2(sm-/-) mice exhibited similar unstable plaque features, aggravated VSMC phenotypic switching, and significant upregulation of Kruppel-like factor 4 (KLF4) in the plaques located in the brachiocephalic arteries compared with those found in Apoe(-/-) and Apoe(-/-)AMPKα2(sm+/+) control mice. Pravastatin, an AMPK activator, suppressed VSMC phenotypic switching and alleviated features of atherosclerotic plaque instability in Apoe(-/-)AMPKα2(sm+/+) mice, but not in Apoe(-/-)AMPKα2(sm-/-) mice. VSMC isolated from AMPKα2(-/-) mice displayed a significant reduction of contractile proteins(smooth muscle actin-α, calponin, and SM-MHC [smooth muscle-mysion heavy chain]) in parallel with increased detection of synthetic proteins (vimentin and osteopontin) and KLF4, as observed in vivo. KLF4-specific siRNA abolished AMPKα2 deletion-induced VSMC phenotypic switching. Furthermore, pharmacological or genetic inhibition of nuclear factor-κB significantly decreased KLF4 upregulation in VSMC from AMPKα2(-/-) mice. Finally, we found that AMPKα2 deletion markedly promoted the binding of nuclear factor-κBp65 to KLF4 promoter.
  
  
  CONCLUSIONS
  This study demonstrated that AMPKα2 deletion induces VSMC phenotypic switching and promotes features of atherosclerotic plaque instability in nuclear factor-κB-KLF4-dependent manner.
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., Q.L., Z.C., P.S., I.S.O., L.X., M.-H.Z.); Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z.); and The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (W.Z.).
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., Q.L., Z.C., P.S., I.S.O., L.X., M.-H.Z.); Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z.); and The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (W.Z.).
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., Q.L., Z.C., P.S., I.S.O., L.X., M.-H.Z.); Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z.); and The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (W.Z.).
authors.forename: Wencheng
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., Q.L., Z.C., P.S., I.S.O., L.X., M.-H.Z.); Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z.); and The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (W.Z.).
authors.forename: Qiulun
authors.initials: Q
authors.lastname: Lu
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., Q.L., Z.C., P.S., I.S.O., L.X., M.-H.Z.); Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z.); and The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (W.Z.).
authors.forename: Zhejun
authors.initials: Z
authors.lastname: Cai
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., Q.L., Z.C., P.S., I.S.O., L.X., M.-H.Z.); Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z.); and The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (W.Z.).
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., Q.L., Z.C., P.S., I.S.O., L.X., M.-H.Z.); Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z.); and The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (W.Z.).
authors.forename: Imoh Sunday
authors.initials: IS
authors.lastname: Okon
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., Q.L., Z.C., P.S., I.S.O., L.X., M.-H.Z.); Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z.); and The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (W.Z.).
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., Q.L., Z.C., P.S., I.S.O., L.X., M.-H.Z.); Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z.); and The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (W.Z.). mzou@gsu.edu.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D066273:Diet, Western / Q000009:adverse effects; D017353:Gene Deletion; D000090062:Kruppel-Like Factor 4; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinases; atherosclerosis