title: Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism.
abstract: Cullin-3 (CUL3) mutations (CUL3Δ9) were previously identified in hypertensive patients with pseudohypoaldosteronism type-II (PHAII), but the mechanism causing hypertension and whether this is driven by renal tubular or extratubular mechanisms remains unknown. We report that selective expression of CUL3Δ9 in smooth muscle acts by interfering with expression and function of endogenous CUL3, resulting in impaired turnover of the CUL3 substrate RhoA, increased RhoA activity, and augmented RhoA/Rho kinase signaling. This caused vascular dysfunction and increased arterial pressure under baseline conditions and a marked increase in arterial pressure, collagen deposition, and vascular stiffness in response to a subpressor dose of angiotensin II, which did not cause hypertension in control mice. Inhibition of total cullin activity increased the level of CUL3 substrates cyclin E and RhoA, and expression of CUL3Δ9 decreased the level of the active form of endogenous CUL3 in human aortic smooth muscle cells. These data indicate that selective expression of theCul3Δ9mutation in vascular smooth muscle phenocopies the hypertension observed inCul3Δ9human subjects and suggest that mutations in CUL3 cause human hypertension in part through a mechanism involving smooth muscle dysfunction initiated by a loss of CUL3-mediated degradation of RhoA.
authors.affiliation: Department of Pharmacology and.
authors.forename: Larry N
authors.initials: LN
authors.lastname: Agbor
authors.affiliation: Department of Pharmacology and.
authors.forename: Stella-Rita C
authors.initials: SC
authors.lastname: Ibeawuchi
authors.affiliation: Department of Pharmacology and.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Pharmacology and.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Davis
authors.affiliation: Department of Pharmacology and.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Keen
authors.affiliation: Department of Pharmacology and.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Quelle
authors.affiliation: Department of Pharmacology and.|UIHC 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: D000818:Animals; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D059289:Vascular Stiffness; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein