Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPARγ and RhoA/Rho-kinase. Cell Metab 2012 Oct 03;16(4):462-72
Date
10/09/2012Pubmed ID
23040068Pubmed Central ID
PMC3474846DOI
10.1016/j.cmet.2012.08.011Scopus ID
2-s2.0-84867084491 (requires institutional sign-in at Scopus site) 84 CitationsAbstract
Dominant-negative (DN) mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ) cause hypertension by an unknown mechanism. Hypertension and vascular dysfunction are recapitulated by expression of DN PPARγ specifically in vascular smooth muscle of transgenic mice. DN PPARγ 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 PPARγ 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 in 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 CDAuthors
Justin L. Grobe PhD Professor in the Physiology department at Medical College of WisconsinCurt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood 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