Journal
FASEB JOURNAL
Volume 29, Issue 8, Pages 3133-3140Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-266064
Keywords
angiotensin II; hypertension; obesity; endothelial NO-synthase
Categories
Funding
- U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases [R37DK43051, R24DK83938, P30DK57521]
- NIH National Heart, Lung, and Blood Institute [HL46457, HL48743]
- German Cardiac Society
- MSD Sharp Dohme, GmbH
- EMBO long-term fellowship
- Manpei Suzuki Diabetes Foundation
- Japan Heart Foundation
- Uehara Medical Foundation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL046457, T32HL007343, P01HL048743, R29HL046457] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK043051, P30DK057521, R37DK043051, R24DK083938] Funding Source: NIH RePORTER
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Elevated levels of serum retinol-binding protein 4 (RBP4) contribute to insulin resistance and correlate with increased prevalence of hypertension and myocardial infarction. We sought to determine whether lowering RBP4 would improve blood pressure (BP) and protect against obesity-or angiotensin (Ang)-II-induced hypertension. Systolic and diastolic BP were lower in the RBP4-knockout (RBP4-KO) mice and higher in the RBP4-overexpressing (RBP4-Tg) mice compared with BP in the wild-type (WT) littermates. Carbachol-induced vasodilatation was increased in arteries from the RBP4-KO compared with the WT mice and was impaired in the RBP4-Tg mice. Aortic eNOS(Ser1177) phosphorylation was enhanced similar to 50% in the RBP4-KO mice, with no change in total eNOS protein. Feeding a high-fat diet increased BP in the RBP4-KO mice only to the level in the WT mice fed chow and had no effect on aortic eNOS(Ser1177) phosphorylation. Ang-II infusion resulted in 22 mmHg lower systolic BP in the RBP4-KO than in the WT mice, although the relative BP increase over saline infusion was similar to 30% in both. Ang-II treatment decreased aortic eNOS(Ser1177) phosphorylation in the WT and RBP4-KO mice, but phosphorylation remained higher in the RBP4-KO mice. Cardiac hypertrophy with Ang-II treatment was diminished by 56% in the RBP4-KO mice. Thus, elevated serum RBP4 raises BP and lack of RBP4 reduces it, with commensurate changes in aortic eNOS(Ser1177) phosphorylation. Lowering RBP4 may reduce BP through enhanced eNOS-mediated vasodilatation and may be a novel therapeutic approach for hypertension.
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