Abstract 10120: Endothelial Cell-specific Lkb1 Deletion Causes Endothelial Dysfunction and Hypertension in Mice In Vivo
Background: Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. The roles of LKB1 in endothelial function in vivo have not been explored.
Methods and Results: The endothelium-specific LKB1 knockout (LKB1endo-/-) mice were generated by crossbreeding LKB1flox/flox mice with VE-cadherin Cre approach. LKB1endo-/- mice exhibited hypertension, cardiac hypertrophy and impaired endothelium-dependent relaxation. In addition, in parallel with reduced levels of both endothelial nitric oxidase (eNOS) activity and phosphorylated (Thr172) AMP-activated protein kinase (AMPK), a downstream enzyme of LKB1, LKB1endo-/- mice expressed high levels of caveolin-1. Further, siRNA silencing of caveolin-1 normalized the eNOS activity in LKB1-deficient endothelial cells. Furthermore, human antigen R (HuR) bound with AU-rich elements of caveolin-1 mRNA 3’ UTR resulting in increased stability of caveolin-1 and genetic knockdown of HuR decreased caveolin-1 level in LKB1-deficient endothelial cells. Finally, we found that inhibition of LKB1 or AMPK induced the translocation of HuR from nuclei to cytosol and overexpression of constitutively active AMPK (CA-AMPK) led to decreased caveolin-1 level. Consistently, administration of CA-AMPK in LKB1endo-/- mice lowered blood pressure with improved endothelial function in vivo.
Conclusions: Our findings indicate that endothelial cell LKB1 plays an essential role in regulating eNOS activity, endothelial function, and blood pressure through modulating AMPK-mediated caveolin-1expression.
- © 2013 by American Heart Association, Inc.