Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism
Larry N. Agbor, … , Frederick W. Quelle, Curt D. Sigmund
Larry N. Agbor, … , Frederick W. Quelle, Curt D. Sigmund
Published November 17, 2016
Citation Information: JCI Insight. 2016;1(19):e91015. https://doi.org/10.1172/jci.insight.91015.
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Research Article Vascular biology

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 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.

Authors

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

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Figure 7

Blood pressure in S-CUL3Δ9 mice.

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Blood pressure in S-CUL3Δ9 mice. (A and B) Systolic blood pressure (A) a...
(A and B) Systolic blood pressure (A) and pulse pressure (B) were measured continuously every 5 minutes for 10 seconds by radiotelemetry for 7 days, starting 2 weeks after tamoxifen in nontransgenic (NT) and S-CUL3Δ9 mice. The data are collapsed onto a single 24-hour-light/dark cycle. Shaded areas indicate the dark cycle. n = 6–7/genotype. *P < 0.05 S-CUL3Δ9 vs. NT by 2-way ANOVA with repeated measurements. (C and D) Effects of acute angiotensin II (Ang II) administration on systolic blood pressure (C) and heart rate (D) in NT and S-CUL3Δ9 mice, as measured by radiotelemetry. Mice were continuously administered Ang II (200 ng/kg/min) through an osmotic minipump for 14 days, and blood pressure was recorded by radiotelemetry as described. Day 1 indicates the start of Ang II infusion. n = 5/genotype. *P < 0.05 S-CUL3Δ9 vs. NT by 2-way ANOVA with repeated measurements.