Journal
NATURE MEDICINE
Volume 11, Issue 9, Pages 952-958Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1289
Keywords
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Funding
- NHLBI NIH HHS [HL 03557] Funding Source: Medline
- NIDA NIH HHS [DA 16347] Funding Source: Medline
- NIDDK NIH HHS [R01 DK 50574, R01 DK 57830, R01 DK057830] Funding Source: Medline
- NIGMS NIH HHS [R01 GM 59989] Funding Source: Medline
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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.
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