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Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism. JCI Insight 2016 Nov 17;1(19):e91015

Date

11/25/2016

Pubmed ID

27882355

Pubmed Central ID

PMC5111503

DOI

10.1172/jci.insight.91015

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 the Cul3Δ9 mutation in vascular smooth muscle phenocopies the hypertension observed in Cul3Δ9 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.

Author List

Agbor LN, Ibeawuchi SC, Hu C, Wu J, Davis DR, Keen HL, Quelle FW, Sigmund CD

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cells, Cultured
Cullin Proteins
Humans
Hypertension
Male
Mice
Mice, Inbred C57BL
Muscle, Smooth, Vascular
Mutation
Myocytes, Smooth Muscle
Vascular Stiffness
rho-Associated Kinases
rhoA GTP-Binding Protein