Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

Larry N Agbor; Stella-Rita C Ibeawuchi; Chunyan Hu; Jing Wu; Deborah R Davis; Henry L Keen; Frederick W Quelle; Curt D Sigmund

doi:10.1172/jci.insight.91015

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Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

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Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

Larry N Agbor, Stella-Rita C Ibeawuchi, Chunyan Hu, Jing Wu, Deborah R Davis, Henry L Keen, Frederick W Quelle and Curt D Sigmund

JCI insight, Vol.1(19), pp.e91015-e91015

11/17/2016

DOI: 10.1172/jci.insight.91015

PMCID: PMC5111503

PMID: 27882355

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Abstract

Cullin-3 ( CUL3 ) mutations ( CUL3 Δ 9 ) 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 the Cul3 Δ 9 mutation in vascular smooth muscle phenocopies the hypertension observed in Cul3 Δ 9 human 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. Smooth muscle-specific expression of a mutant form of Cullin-3 causes vascular dysfunction and hypertension, and augments the pressor response to angiotensin-II.

Details

Title: Subtitle: Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism
Creators: Larry N Agbor - Department of Pharmacology and
Stella-Rita C Ibeawuchi - Department of Pharmacology and
Chunyan Hu - Department of Pharmacology and
Jing Wu - Department of Pharmacology and
Deborah R Davis - Department of Pharmacology and
Henry L Keen - Department of Pharmacology and
Frederick W Quelle - Department of Pharmacology and
Curt D Sigmund - Department of Pharmacology and
Resource Type: Journal article
Publication Details: JCI insight, Vol.1(19), pp.e91015-e91015
Publisher: American Society for Clinical Investigation
DOI: 10.1172/jci.insight.91015
PMID: 27882355
PMCID: PMC5111503
ISSN: 2379-3708
eISSN: 2379-3708
Language: English
Date published: 11/17/2016
Academic Unit: Molecular Physiology and Biophysics; Pathology; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984040383402771

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