Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances α 1D -adrenergic receptor constriction

Heather Irina Cohn, David M. Harris, Stephanie Pesant, Michael Pfeiffer, Rui Hai Zhou, Walter J. Koch, Gerald W. Dorn, Andrea D. Eckhart

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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 carboxylterminal 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, α 1 AR-mediated vasoconstriction was also increased. Further pharmacological experiments using α 1 AR antagonists revealed that GRK2 inhibition of expression (GRK2KO) or activity (GRK2ct) enhanced α 1D AR vasoconstriction. This is the first study to suggest that VSM α 1D ARs are a GRK2 substrate in vivo.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number4
DOIs
StatePublished - Oct 1 2008

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G-Protein-Coupled Receptor Kinase 2
Muscle Proteins
Vascular Smooth Muscle
Constriction
Adrenergic Receptors
Blood Pressure
Vasoconstriction
Hypertension
Animal Disease Models
Renal Artery Obstruction
Adrenergic Antagonists
Protein-Serine-Threonine Kinases
G-Protein-Coupled Receptors
Surgical Instruments
Vasodilation
Dilatation
Norepinephrine
Heart Failure

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Cohn, Heather Irina ; Harris, David M. ; Pesant, Stephanie ; Pfeiffer, Michael ; Zhou, Rui Hai ; Koch, Walter J. ; Dorn, Gerald W. ; Eckhart, Andrea D. / Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances α 1D -adrenergic receptor constriction In: American Journal of Physiology - Heart and Circulatory Physiology. 2008 ; Vol. 295, No. 4.
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abstract = "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 carboxylterminal 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, α 1 AR-mediated vasoconstriction was also increased. Further pharmacological experiments using α 1 AR antagonists revealed that GRK2 inhibition of expression (GRK2KO) or activity (GRK2ct) enhanced α 1D AR vasoconstriction. This is the first study to suggest that VSM α 1D ARs are a GRK2 substrate in vivo.",
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Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances α 1D -adrenergic receptor constriction . / Cohn, Heather Irina; Harris, David M.; Pesant, Stephanie; Pfeiffer, Michael; Zhou, Rui Hai; Koch, Walter J.; Dorn, Gerald W.; Eckhart, Andrea D.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 295, No. 4, 01.10.2008.

Research output: Contribution to journalArticle

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T1 - Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances α 1D -adrenergic receptor constriction

AU - Cohn, Heather Irina

AU - Harris, David M.

AU - Pesant, Stephanie

AU - Pfeiffer, Michael

AU - Zhou, Rui Hai

AU - Koch, Walter J.

AU - Dorn, Gerald W.

AU - Eckhart, Andrea D.

PY - 2008/10/1

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N2 - 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 carboxylterminal 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, α 1 AR-mediated vasoconstriction was also increased. Further pharmacological experiments using α 1 AR antagonists revealed that GRK2 inhibition of expression (GRK2KO) or activity (GRK2ct) enhanced α 1D AR vasoconstriction. This is the first study to suggest that VSM α 1D ARs are a GRK2 substrate in vivo.

AB - 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 carboxylterminal 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, α 1 AR-mediated vasoconstriction was also increased. Further pharmacological experiments using α 1 AR antagonists revealed that GRK2 inhibition of expression (GRK2KO) or activity (GRK2ct) enhanced α 1D AR vasoconstriction. This is the first study to suggest that VSM α 1D ARs are a GRK2 substrate in vivo.

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