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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/H1695    most recent 00564.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Cohn, H. I. Articles by Eckhart, A. D. Search for Related Content PubMed PubMed Citation Articles by Cohn, H. I. Articles by Eckhart, A. D.

Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances _1D-adrenergic receptor constriction

¹Center for Translational Medicine, ²Eugene Feiner Laboratory for Vascular Biology and Thrombosis, Department of Medicine, and ³George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Thomas Jefferson University, Philadelphia, Pennsylvania; and ⁴Cardiovascular Research Center Washington University School of Medicine, St. Louis, Missouri

Submitted 27 May 2008 ; accepted in final form 4 August 2008

G protein-coupled receptor kinase 2 (GRK2) is a serine/theorinine kinase that phosphorylates and desensitizes agonist-bound G protein-coupled receptors. GRK2 is increased in expression and activity in lymphocytes and vascular smooth muscle (VSM) in human hypertension and animal models of the disease. Inhibition of GRK2 using the carboxyl-terminal portion of the protein (GRK2ct) has been an effective tool to restore compromised β-adrenergic receptor (AR) function in heart failure and improve outcome. A well-characterized dysfunction in hypertension is attenuation of βAR-mediated vasodilation. Therefore, we tested the role of inhibition of GRK2 using GRK2ct or VSM-selective GRK2 gene ablation in a renal artery stenosis model of elevated blood pressure (BP) [the two-kidney, one-clip (2K1C) model]. Use of the 2K1C model resulted in a 30% increase in conscious BP, a threefold increase in plasma norepinephrine levels, and a 50% increase in VSM GRK2 mRNA levels. BP remained increased despite VSM-specific GRK2 inhibition by either GRK2 knockout (GRK2KO) or peptide inhibition (GRK2ct). Although βAR-mediated dilation in vivo and in situ was enhanced, ₁AR-mediated vasoconstriction was also increased. Further pharmacological experiments using ₁AR antagonists revealed that GRK2 inhibition of expression (GRK2KO) or activity (GRK2ct) enhanced _1DAR vasoconstriction. This is the first study to suggest that VSM _1DARs are a GRK2 substrate in vivo.

phenylephrine; hypertension; transgenic mice; gene ablation

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