Nature Medicine
11, 952 - 958 (2005)
Published online: 4 September 2005; | doi:10.1038/nm1289
A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertensionSongling Liu1, 2, 4, Richard T Premont2, Christopher D Kontos2, 3, Shoukang Zhu2
& Don C Rockey1, 2, 41
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. 2
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. 3
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA. 4
Present address: University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. (S.L., D.C.R.).
Correspondence should be addressed to Don C Rockey don.rockey@utsouthwestern.edu Nitric oxide (NO) production by endothelial cell nitric oxide synthase (eNOS) in sinusoidal endothelial cells is reduced in the injured liver and leads to intrahepatic portal hypertension. We sought to understand the mechanism underlying defective eNOS function. Phosphorylation of the serine-threonine kinase Akt, which activates eNOS, was substantially reduced in sinusoidal endothelial cells from injured livers. Overexpression of Akt in vivo restored phosphorylation of Akt and production of NO and reduced portal pressure in portal hypertensive rats. We found that Akt physically interacts with G-protein-coupled receptor kinase-2 (GRK2), and that this interaction inhibits Akt activity. Furthermore, GRK2 expression increased in sinusoidal endothelial cells from portal hypertensive rats and knockdown of GRK2 restored Akt phosphorylation and NO production, and normalized portal pressure. Finally, after liver injury, GRK2-deficient mice developed less severe portal hypertension than control mice. Thus, an important mechanism underlying impaired activity of eNOS in injured sinusoidal endothelial cells is defective phosphorylation of Akt caused by overexpression of GRK2 after injury.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
