title: Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPARγ and RhoA/Rho-kinase.
abstract: Dominant-negative (DN) mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ) cause hypertension by an unknown mechanism. Hypertension and vascular dysfunction are recapitulated by expression of DN PPARγ specifically in vascular smooth muscle of transgenic mice. DN PPARγ increases RhoA and Rho-kinase activity, and inhibition of Rho-kinase restores normal reactivity and reduces arterial pressure. RhoBTB1, a component of the Cullin-3 RING E3 ubiquitin ligase complex, is a PPARγ target gene. Decreased RhoBTB1, Cullin-3, and neddylated Cullin-3 correlated with increased levels of the Cullin-3 substrate RhoA. Knockdown of Cullin-3 or inhibition of cullin-RING ligase activity in aortic smooth muscle cells increased RhoA. Cullin-RING ligase inhibition enhanced agonist-mediated contraction in aortic rings from normal mice by a Rho-kinase-dependent mechanism, and it increased arterial pressure in vivo. We conclude that Cullin-3 regulates vascular function and arterial pressure, thus providing a mechanistic link between mutations in Cullin-3 and hypertension in humans.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Pelham
authors.forename: Pimonrat
authors.initials: P
authors.lastname: Ketsawatsomkron
authors.forename: Séverine
authors.initials: S
authors.lastname: Groh
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.forename: Willem J
authors.initials: WJ
authors.lastname: de Lange
authors.forename: Stella-Rita C
authors.initials: SR
authors.lastname: Ibeawuchi
authors.forename: Henry L
authors.initials: HL
authors.lastname: Keen
authors.forename: Eric T
authors.initials: ET
authors.lastname: Weatherford
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein