Novel role for retinol-binding protein 4 in the regulation of blood pressure.
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 ∼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 ∼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.
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Bettina J
BJ
Kraus
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Juliano L
JL
Sartoretto
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Pazit
P
Polak
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Tetsuya
T
Hosooka
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Takashi
T
Shiroto
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Iratxe
I
Eskurza
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Seung-Ah
SA
Lee
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Hongfeng
H
Jiang
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Thomas
T
Michel
*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA bkahn@bidmc.harvard.edu.
Barbara B
BB
Kahn
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology*; D006332:Cardiomegaly / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology
C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; D000804:Angiotensin II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
angiotensin II; endothelial NO-synthase; hypertension; obesity