| First Author | Zhang W | Year | 2014 |
| Journal | Circulation | Volume | 129 |
| Issue | 13 | Pages | 1428-39 |
| PubMed ID | 24637557 | Mgi Jnum | J:219306 |
| Mgi Id | MGI:5620078 | Doi | 10.1161/CIRCULATIONAHA.113.004146 |
| Citation | Zhang W, et al. (2014) Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo. Circulation 129(13):1428-39 |
| abstractText | 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. |
