Endothelial Cell–Specific Liver Kinase B1 Deletion Causes Endothelial Dysfunction and Hypertension in Mice In VivoCLINICAL PERSPECTIVE
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 (LKB1endo−/−) mice were generated by cross-breeding LKB1flox/flox mice with VE-Cadherin-Cre mice. LKB1endo−/− mice exhibited hypertension, cardiac hypertrophy, and impaired endothelium-dependent relaxation. LKB1endo−/− 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 LKB1endo−/− 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 LKB1endo−/− 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.
- Received May 29, 2013.
- Accepted January 8, 2014.
- © 2014 American Heart Association, Inc.