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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
12
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pubmed:dateCreated |
2003-12-3
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pubmed:abstractText |
Nitric oxide (NO) inhibits vascular contraction by activating cGMP-dependent protein kinase I-alpha (PKGI-alpha), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-alpha attenuates signaling by the thrombin receptor protease-activated receptor-1 (PAR-1) through direct activation of regulator of G-protein signaling-2 (RGS-2). NO donors and cGMP cause cGMP-mediated inhibition of PAR-1 and membrane localization of RGS-2. PKGI-alpha binds directly to and phosphorylates RGS-2, which significantly increases GTPase activity of G(q), terminating PAR-1 signaling. Disruption of the RGS-2-PKGI-alpha interaction reverses inhibition of PAR-1 signaling by nitrovasodilators and cGMP. Rgs2-/- mice develop marked hypertension, and their blood vessels show enhanced contraction and decreased cGMP-mediated relaxation. Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. Our study shows that RGS-2 is required for normal vascular function and blood pressure and is a new drug development target for hypertension.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1078-8956
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pubmed:author |
pubmed-author:AronovitzMarkM,
pubmed-author:BlumerKendall JKJ,
pubmed-author:HeximerScott PSP,
pubmed-author:KaltenbronnKevin MKM,
pubmed-author:KarasRichard HRH,
pubmed-author:KwoO SOS,
pubmed-author:LuPingP,
pubmed-author:MendelsohnMichael EME,
pubmed-author:SiderovskiDavid PDP,
pubmed-author:TangK MaryKM,
pubmed-author:TangMaryM,
pubmed-author:WangGuang-rongGR,
pubmed-author:WangGuangG
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pubmed:issnType |
Print
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pubmed:volume |
9
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1506-12
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:14608379-Animals,
pubmed-meshheading:14608379-Blood Pressure,
pubmed-meshheading:14608379-Cell Line,
pubmed-meshheading:14608379-Cyclic GMP-Dependent Protein Kinases,
pubmed-meshheading:14608379-Humans,
pubmed-meshheading:14608379-Mice,
pubmed-meshheading:14608379-Mice, Knockout,
pubmed-meshheading:14608379-Muscle, Smooth, Vascular,
pubmed-meshheading:14608379-Muscle Relaxation,
pubmed-meshheading:14608379-RGS Proteins,
pubmed-meshheading:14608379-Rats,
pubmed-meshheading:14608379-Receptor, PAR-1,
pubmed-meshheading:14608379-Signal Transduction
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pubmed:year |
2003
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pubmed:articleTitle |
Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure.
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pubmed:affiliation |
Molecular Cardiology Research Institute, New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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