Dataset Information

Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPAR? and RhoA/Rho-kinase.

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

SUBMITTER: Pelham CJ

PROVIDER: S-EPMC3474846 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPARγ and RhoA/Rho-kinase.

Pelham Christopher J CJ Ketsawatsomkron Pimonrat P Groh Séverine S Grobe Justin L JL de Lange Willem J WJ Ibeawuchi Stella-Rita C SR Keen Henry L HL Weatherford Eric T ET Faraci Frank M FM Sigmund Curt D CD

Cell metabolism 20121001 4

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 ...[more]

PMID: 23040068

Similar Datasets

Project description:Depolarization of the sarcolemma of smooth muscle cells activates voltage-gated Ca2+ channels, influx of Ca2+ and activation of cross-bridge cycling by phosphorylation of myosin catalysed by Ca2+/calmodulin-dependent myosin light-chain kinase (MLCK). Agonist stimulation of smooth muscle contraction often involves other kinases in addition to MLCK. In the present study, we address the hypothesis that membrane depolarization-induced contraction of rat caudal arterial smooth muscle may involve activation of Rho-associated kinase (ROK). Addition of 60 mM K+ to de-endothelialized muscle strips in the presence of prazosin and propranolol induced a contraction that peaked rapidly and then declined to a steady level of force corresponding to approx. 30% of the peak contraction. This contractile response was abolished by the Ca2+-channel blocker nicardipine or the removal of extracellular Ca2+. An MLCK inhibitor (ML-9) inhibited both the phasic and tonic components of K+-induced contraction. On the other hand, the ROK inhibitors Y-27632 and HA-1077 abolished the tonic component of K+-induced contraction, and slightly reduced the phasic component. Phosphorylation levels of the 20-kDa light chain of myosin increased rapidly in response to 60 mM K+ and subsequently declined to a steady-state level significantly greater than the resting level. Y-27632 abolished the sustained and reduced the phasic elevation of the phosphorylation of the 20-kDa light chain of myosin, without affecting the K+-induced elevation of cytosolic free Ca2+ concentration. These results indicate that ROK activation plays an important role in the sustained phase of K+-induced contraction of rat caudal arterial smooth muscle, but has little involvement in the phasic component of K+-induced contraction. Furthermore, these results are consistent with inhibition of myosin light-chain phosphatase by ROK, which would account for the sustained elevation of myosin phosphorylation and tension in response to membrane depolarization.

Dataset Information

Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPAR? and RhoA/Rho-kinase.

Publications

Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPARγ and RhoA/Rho-kinase.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets