Journal
CIRCULATION
Volume 129, Issue 13, Pages 1428-1439Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.113.004146
Keywords
AMP-activated protein kinases; caveolin 1; hypertension; nitric oxide synthase type III
Funding
- National Institutes of Health [HL074399, HL080499, HL089920, HL110488, HL105157]
- Warren Chair in Diabetes Research at the University of Oklahoma Health Science Center
- American Heart Association
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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.
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