Retinol-binding protein 7 is an endothelium-specific PPARγ cofactor mediating an antioxidant response through adiponectin
Chunyan Hu, … , Frederick W. Quelle, Curt D. Sigmund
Chunyan Hu, … , Frederick W. Quelle, Curt D. Sigmund
Published March 23, 2017
Citation Information: JCI Insight. 2017;2(6):e91738. https://doi.org/10.1172/jci.insight.91738.
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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 1

Endothelial specificity of retinol-binding protein 7 (RBP7).

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Endothelial specificity of retinol-binding protein 7 (RBP7). (A) Endothe...
(A) Endothelial (EC+) and non–endothelial (EC–) cells were magnetically sorted from dissociated single cells isolated from kidney, lung, and aorta from control and RBP7-deficient mice. RBP7 expression was measured by quantitative real-time RT-PCR. *P < 0.05 EC+ vs. EC– cells by Student’s t test. n = 6–7 per group in kidney and lung, and 3–12 in aorta. (B) Expression of RBP7 mRNA was measured in mouse lung endothelial cells (MLECs) in response to 24 hours of the indicated dose of rosiglitazone (Rosi) or vehicle (DMSO) in the absence or presence of GW9662 (10 μM). *P < 0.05 Rosi (1.0 μM) vs. DMSO; #P < 0.05 GW9662 vs. Rosi (1.0 μM) by 1-way ANOVA; n = 3 per group. (C) The level of RBP7 protein was measured by Western blot from MLECs treated with vehicle or Rosi (10 μM) for 24 hours that were infected with either adenovirus expressing GFP (AdGFP) or PPARγ (AdPPARγ) (see supplemental methods). Representative of 3 independent experiments. (D) The level of RBP7 protein was measured by Western blot from MLECs infected for 72 hours with either AdGFP or AdPPARγ at the indicated multiplicity of infection. The decrease in PPARγ expression in the highest dose is due to cell death. Representative of 4 independent experiments.