title: Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo.
abstract: BACKGROUND
  Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. The role of LKB1 in endothelial function in vivo has not been explored.
  
  
  RESULTS
  Endothelium-specific LKB1 knockout (LKB1(endo-/-)) mice were generated by cross-breeding LKB1(flox/flox) mice with VE-Cadherin-Cre mice. LKB1(endo-/-) mice exhibited hypertension, cardiac hypertrophy, and impaired endothelium-dependent relaxation. LKB1(endo-/-) endothelial cells exhibited reduced endothelial nitric oxide synthase activity and AMP kinase (a downstream enzyme of LKB1) phosphorylation at Thr172 compared with wild-type (WT) cells. In addition, the levels of caveolin-1 were higher in the endothelial cells of LKB1(endo-/-) mice, and knockdown of caveolin-1 by siRNA normalized endothelial nitric oxide synthase activity. Human antigen R bound with the adenylate-uridylate-rich elements of caveolin-1 mRNA 3' untranslated region, resulting in the increased stability of caveolin-1, and genetic knockdown of human antigen R decreased the expression of caveolin-1 in LKB1-deficient endothelial cells. Finally, adenoviral overexpression of constitutively active AMP kinase, but not green fluorescent protein, decreased caveolin-1, lowered blood pressure, and improved endothelial function in LKB1(endo-/-) mice in vivo.
  
  
  CONCLUSIONS
  Our findings indicate that endothelial LKB1 regulates endothelial nitric oxide synthase activity, endothelial function, and blood pressure by modulating AMP kinase-mediated caveolin-1 expression.
authors.affiliation: Section of Molecular Medicine, Department of Medicine (W.Z., Q.W., Y.W., C.M., Z.L., X.D., Q.W., M.-H.Z.) and Department of Biochemistry and Molecular Biology (Z.L., M.-H.Z.), University of Oklahoma Health Sciences Center, Oklahoma City; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, China (Y.W., W.L., Z.-Y.Y., M.-H.Z.); and Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China (M.-H.Z.).
authors.forename: Wencheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Qilong
authors.initials: Q
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.forename: Cate
authors.initials: C
authors.lastname: Moriasi
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Liu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Dai
authors.forename: Qiongxin
authors.initials: Q
authors.lastname: Wang
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.forename: Zu-Yi
authors.initials: ZY
authors.lastname: Yuan
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D051242:Caveolin 1 / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D017353:Gene Deletion; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051242:Caveolin 1; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase
keywords: AMP-activated protein kinases; caveolin 1; hypertension; nitric oxide synthase type III