Retinol-binding protein 7 is an endothelium-specific PPARγ cofactor mediating an antioxidant response through adiponectin
Chunyan Hu, Henry L. Keen, Ko-Ting Lu, Xuebo Liu, Jing Wu, Deborah R. Davis, Stella-Rita C. Ibeawuchi, Silke Vogel, Frederick W. Quelle, Curt D. Sigmund
Chunyan Hu, Henry L. Keen, Ko-Ting Lu, Xuebo Liu, Jing Wu, Deborah R. Davis, Stella-Rita C. Ibeawuchi, Silke Vogel, Frederick W. Quelle, Curt D. Sigmund
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Research Article Vascular biology

Retinol-binding protein 7 is an endothelium-specific PPARγ cofactor mediating an antioxidant response through adiponectin

Abstract

Impaired PPARγ activity in endothelial cells causes oxidative stress and endothelial dysfunction which causes a predisposition to hypertension, but the identity of key PPARγ target genes that protect the endothelium remain unclear. Retinol-binding protein 7 (RBP7) is a PPARγ target gene that is essentially endothelium specific. Whereas RBP7-deficient mice exhibit normal endothelial function at baseline, they exhibit severe endothelial dysfunction in response to cardiovascular stressors, including high-fat diet and subpressor angiotensin II. Endothelial dysfunction was not due to differences in weight gain, impaired glucose homeostasis, or hepatosteatosis, but occurred through an oxidative stress–dependent mechanism which can be rescued by scavengers of superoxide. RNA sequencing revealed that RBP7 was required to mediate induction of a subset of PPARγ target genes by rosiglitazone in the endothelium including adiponectin. Adiponectin was selectively induced in the endothelium of control mice by high-fat diet and rosiglitazone, whereas RBP7 deficiency abolished this induction. Adiponectin inhibition caused endothelial dysfunction in control vessels, whereas adiponectin treatment of RBP7-deficient vessels improved endothelium-dependent relaxation and reduced oxidative stress. We conclude that RBP7 is required to mediate the protective effects of PPARγ in the endothelium through adiponectin, and RBP7 is an endothelium-specific PPARγ target and regulator of PPARγ activity.

Authors

Chunyan Hu, Henry L. Keen, Ko-Ting Lu, Xuebo Liu, Jing Wu, Deborah R. Davis, Stella-Rita C. Ibeawuchi, Silke Vogel, Frederick W. Quelle, Curt D. Sigmund

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Figure 5

Role of RBP7 in response to Ang-II.

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Role of RBP7 in response to Ang-II. (A) Systolic BP was measured in cont...
(A) Systolic BP was measured in control and RBP7-deficient mice at baseline by tail cuff. This is an independent replication cohort from that shown in Figure 1 to ensure that experiments performed at different times had similar range of BPs (n = 22, not significant by Student’s t test). (B) A subset of the mice used in panels C and D were first treated with a subpressor dose of Ang-II (120 ng/kg/min, 2 weeks) or vehicle (isotonic saline) and BP was measured by tail cuff to confirm the absence of a pressor response (n = 6, not significant by ANOVA). The robust hypertensive response to a pressor dose of Ang-II is shown in Supplemental Figure 4. (C and D) Vasodilation of the carotid artery from control and RBP7-deficient mice treated with vehicle or subpressor Ang-II was measured in response to acetylcholine (ACh) (C) and sodium nitroprusside (SNP) (D) *P < 0.05 vs. RBP7–Ang-II by 2-way repeated measures (RM) ANOVA; n = 5–8 per group. (E and F) Representative dihydroethidium (DHE, E) fluorescence and nitrotyrosine immunofluorescence (F) staining conducted in carotid arteries from vehicle or Ang-II–infused control or RBP7-deficient mice. White arrows indicate nitrotyrosine-positive endothelial cells that costain with CD31. Scale bars: 100 μm (E) and 50 μm (F). Quantification of independent replicates is shown. *P < 0.05 RBP7 vs. control; #P < 0.05 RBP7–Ang-II vs. RBP7-vehicle by 2-way ANOVA; n = 4 per group. (G) Vasodilation of the carotid artery from control and RBP7-deficient mice infused with subpressor Ang-II for 2 weeks in the presence or absence of Tempol (1 mmol/l, 30 minutes) was measured in response to ACh. *P < 0.05 vs. all other curves by 2-way RM ANOVA; n = 5 per group. All data are the mean ± SEM. Ang-II, angiotensin II; RBP7, retinol-binding protein 7; V, vehicle; Con, control.