Document Detail


Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPARγ and RhoA/Rho-kinase.
MedLine Citation:
PMID:  23040068     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Christopher J Pelham; Pimonrat Ketsawatsomkron; Séverine Groh; Justin L Grobe; Willem J de Lange; Stella-Rita C Ibeawuchi; Henry L Keen; Eric T Weatherford; Frank M Faraci; Curt D Sigmund
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell metabolism     Volume:  16     ISSN:  1932-7420     ISO Abbreviation:  Cell Metab.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-08     Completed Date:  2013-03-07     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  101233170     Medline TA:  Cell Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  462-72     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Pressure / physiology
Cullin Proteins / antagonists & inhibitors,  genetics,  metabolism*
HEK293 Cells
Humans
Mice
Mice, Transgenic
Muscle, Smooth, Vascular / metabolism*
PPAR gamma / antagonists & inhibitors,  metabolism*
RNA Interference
RNA, Small Interfering / metabolism
Transfection
rho-Associated Kinases / metabolism*
rhoA GTP-Binding Protein / metabolism*
Grant Support
ID/Acronym/Agency:
HL038901/HL/NHLBI NIH HHS; HL048058/HL/NHLBI NIH HHS; HL061446/HL/NHLBI NIH HHS; HL062984/HL/NHLBI NIH HHS; HL084207/HL/NHLBI NIH HHS; HL098276/HL/NHLBI NIH HHS; K99 HL098276/HL/NHLBI NIH HHS; NS024621/NS/NINDS NIH HHS; P01 HL062984/HL/NHLBI NIH HHS; P01 HL084207/HL/NHLBI NIH HHS; P01 NS024621/NS/NINDS NIH HHS; R00 HL098276/HL/NHLBI NIH HHS; R01 HL038901/HL/NHLBI NIH HHS; R01 HL061446/HL/NHLBI NIH HHS; R37 HL048058/HL/NHLBI NIH HHS; T32 GM067795/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Cul3 protein, mouse; 0/Cullin Proteins; 0/PPAR gamma; 0/RNA, Small Interfering; EC 2.7.11.1/rho-Associated Kinases; EC 3.6.5.2/rhoA GTP-Binding Protein
Comments/Corrections
Comment In:
Cell Metab. 2012 Oct 3;16(4):410-1   [PMID:  23040065 ]

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