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 role of LKB1 in endothelial function in vivo has not been explored.
Methods and Results—Endothelium-specific LKB1 knockout (LKB1endo-/-) mice were generated by crossbreeding 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 (eNOS) activity and adenosine monophosphate-activated protein kinase (AMPK; downstream enzyme of LKB1) phosphorylation at Thr172, compared with those of 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 eNOS activity. Human antigen R (HuR) bound with the AU-rich elements of caveolin-1 mRNA 3' UTR, resulting in the increased stability of caveolin-1, and genetic knockdown of HuR decreased the expression of caveolin-1 in LKB1-deficient endothelial cells. Finally, adenoviral overexpression of constitutively active AMPK (CA-AMPK), but not green fluorescent protein (GFP), decreased caveolin-1, lowered blood pressure, and improved endothelial function in LKB1endo-/- mice in vivo.
Conclusions—Our findings indicate that endothelial LKB1 regulates eNOS activity, endothelial function, and blood pressure by modulating AMPK-mediated caveolin-1 expression.
- Received May 29, 2013.
- Revision received December 17, 2013.
- Accepted January 8, 2014.