Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPARI? and RhoA/Rho-kinase. Cell Metab 2012 Oct 03;16(4):462-72

Date

10/09/2012

Pubmed ID

23040068

Pubmed Central ID

PMC3474846

DOI

10.1016/j.cmet.2012.08.011

Scopus ID

2-s2.0-84867084491   76 Citations

Abstract

Dominant-negative (DN) mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor-I? (PPARI?) cause hypertension by an unknown mechanism. Hypertension and vascular dysfunction are recapitulated by expression of DN PPARI? specifically in vascular smooth muscle of transgenic mice. DN PPARI? 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 PPARI? 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 inA 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.

Author List

Pelham CJ, Ketsawatsomkron P, Groh S, Grobe JL, de Lange WJ, Ibeawuchi SR, Keen HL, Weatherford ET, Faraci FM, Sigmund CD

Authors

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin
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
Blood Pressure
Cullin Proteins
HEK293 Cells
Humans
Mice
Mice, Transgenic
Muscle, Smooth, Vascular
PPAR gamma
RNA Interference
RNA, Small Interfering
Transfection
rho-Associated Kinases
rhoA GTP-Binding Protein