title: Retinol-binding protein 7 is an endothelium-specific PPARγcofactor 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.affiliation: Department of Pharmacology.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Pharmacology.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Keen
authors.affiliation: Department of Pharmacology.
authors.forename: Ko-Ting
authors.initials: KT
authors.lastname: Lu
authors.affiliation: Department of Pharmacology.
authors.forename: Xuebo
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pharmacology.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Davis
authors.affiliation: Department of Pharmacology.
authors.forename: Stella-Rita C
authors.initials: SC
authors.lastname: Ibeawuchi
authors.affiliation: Duke-NUS Medical School, Singapore, Singapore.
authors.forename: Silke
authors.initials: S
authors.lastname: Vogel
authors.affiliation: Department of Pharmacology.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Quelle
authors.affiliation: Department of Pharmacology.|UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D059305:Diet, High-Fat; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D054840:Retinol-Binding Proteins, Cellular / Q000235:genetics / Q000378:metabolism*
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D000975:Antioxidants; D047495:PPAR gamma; D012333:RNA, Messenger; C521400:Rbp7 protein, mouse; D054840:Retinol-Binding Proteins, Cellular