Journal article
Cullin-3 Regulates Vascular Smooth Muscle Function and Arterial Blood Pressure via PPARγ and RhoA/Rho-Kinase
Cell metabolism, Vol.16(4), pp.462-472
10/03/2012
DOI: 10.1016/j.cmet.2012.08.011
PMCID: PMC3474846
PMID: 23040068
Abstract
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.
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► Interference with PPARγ in smooth muscle increases RhoA/Rho-kinase activity ► RhoBTB1 is a PPARγ target gene that acts in concert with Cullin-3 ► Knockdown of Cullin-3 or inhibition of cullin-RING ligase activity increases RhoA ► Cullin-RING ligase inhibition increases vascular contraction and arterial pressure
Details
- Title: Subtitle
- Cullin-3 Regulates Vascular Smooth Muscle Function and Arterial Blood Pressure via PPARγ and RhoA/Rho-Kinase
- Creators
- Christopher J Pelham - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USAPimonrat Ketsawatsomkron - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USASéverine Groh - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USAJustin L Grobe - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USAWillem J de Lange - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USAStella-Rita C Ibeawuchi - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USAHenry L Keen - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USAEric T Weatherford - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USAFrank M Faraci - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USACurt D Sigmund - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USA
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.16(4), pp.462-472
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.cmet.2012.08.011
- PMID
- 23040068
- PMCID
- PMC3474846
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Language
- English
- Date published
- 10/03/2012
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Neuroscience and Pharmacology; Endocrinology and Metabolism; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984040595502771
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