Wencheng Zhang1, Qilong Wang, Yue Wu, Cate Moriasi, Zhaoyu Liu, Xiaoyan Dai, Qiongxin Wang, Weimin Liu, Zu-Yi Yuan, Ming-Hui Zou. 1. 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.).
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. METHODS AND 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.
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. METHODS AND 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.
Entities:
Keywords:
AMP-activated protein kinases; caveolin 1; hypertension; nitric oxide synthase type III
Authors: Guanghong Jia; Javad Habibi; Annayya R Aroor; Luis A Martinez-Lemus; Vincent G DeMarco; Francisco I Ramirez-Perez; Zhe Sun; Melvin R Hayden; Gerald A Meininger; Katelee Barrett Mueller; Iris Z Jaffe; James R Sowers Journal: Circ Res Date: 2016-02-15 Impact factor: 17.367