![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 61, Issue 4, 749-758, April 2002
-Adrenergic Receptor
Signaling and Increases Resting Blood Pressure
Department of Surgery (A.D.E., H.T., W.J.K.) and
Department of Medicine (Cardiology) (T.O., H.A.R.), Duke University
Medical Center, Durham, North Carolina
Cardiovascular regulation is tightly controlled by signaling through G
protein-coupled receptors (GPCRs). 
-Adrenergic receptors (ARs) are
GPCRs that regulate inotropy and chronotropy in the heart and mediate
vasodilation, which critically influences systemic vascular resistance.
GPCR kinases (GRKs), including GRK2 (or ARK1), phosphorylate and
desensitize agonist-activated ARs. Myocardial GRK2 levels are
increased in heart failure and data suggest that vascular levels may
also be elevated in hypertension. Therefore, we generated transgenic
mice with vascular smooth muscle (VSM) targeted overexpression of GRK2,
using a portion of the SM22
promoter, to determine its impact on
vascular AR regulation. VSM AR signaling, as determined by
adenylyl cyclase and mitogen-activated protein (MAP) kinase activation
assays, was attenuated when GRK2 was overexpressed 2- to 3-fold. In
vivo vasodilation in response to AR stimulation using isoproterenol
was attenuated and conscious resting mean arterial blood pressure was
elevated from 96 ± 2 mm Hg in nontransgenic littermate control
(NLC) mice (n = 9) to 112 ± 3 mm Hg and
117 ± 2 mm Hg in two different lines of SM22-GRK2 transgenic
mice (n = 7 and n = 5, respectively; p < 0.05). Interestingly, medial VSM
thickness was increased 30% from 29.8 ± 1.6 µm in NLC mice
(n = 6) to 39.4 ± 1.6 µm in SM22-GRK2
mice (n = 7) (p < 0.05) and
vascular GRK2 overexpression was sufficient to cause cardiac
hypertrophy. These data indicate that we have developed a unique mouse
model of hypertension, providing insight into the contribution that
vascular AR signaling makes toward resting blood pressure and
overall cardiovascular regulation. Moreover, they suggest that GRK2
plays an important role in vascular control and may represent a novel
therapeutic target for hypertension.
This article has been cited by other articles:
|
|
 |
|
  H. I. Cohn, Y. Xi, S. Pesant, D. M. Harris, T. Hyslop, B. Falkner, and A. D. Eckhart G Protein-Coupled Receptor Kinase 2 Expression and Activity Are Associated With Blood Pressure in Black Americans Hypertension, July 1, 2009; 54(1): 71 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Oliver, D. Marti, F. Monto, N. Flacco, L. Moreno, D. Barettino, M. D. Ivorra, and P. D'Ocon The Impact of {alpha}1-Adrenoceptors Up-Regulation Accompanied by the Impairment of {beta}-Adrenergic Vasodilatation in Hypertension J. Pharmacol. Exp. Ther., March 1, 2009; 328(3): 982 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. I. Cohn, D. M. Harris, S. Pesant, M. Pfeiffer, R.-H. Zhou, W. J. Koch, G. W. Dorn 2nd, and A. D. Eckhart Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances {alpha}1D-adrenergic receptor constriction Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1695 - H1704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zeng, V. A. M. Villar, G. M. Eisner, S. M. Williams, R. A. Felder, and P. A. Jose G Protein-Coupled Receptor Kinase 4: Role in Blood Pressure Regulation Hypertension, June 1, 2008; 51(6): 1449 - 1455. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Cho, C. Park, I.-Y. Hwang, S.-B. Han, D. Schimel, D. Despres, and J. H. Kehrl Rgs5 Targeting Leads to Chronic Low Blood Pressure and a Lean Body Habitus Mol. Cell. Biol., April 15, 2008; 28(8): 2590 - 2597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Pleger, D. M. Harris, C. Shan, L. E. Vinge, J. K. Chuprun, B. Berzins, W. Pleger, C. Druckman, M. Volkers, J. Heierhorst, et al. Endothelial S100A1 Modulates Vascular Function via Nitric Oxide Circ. Res., April 11, 2008; 102(7): 786 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Harris, H. I. Cohn, S. Pesant, R.-H. Zhou, and A. D. Eckhart Vascular smooth muscle Gq signaling is involved in high blood pressure in both induced renal and genetic vascular smooth muscle-derived models of hypertension Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3072 - H3079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Leosco, G. Rengo, G. Iaccarino, A. Filippelli, A. Lymperopoulos, C. Zincarelli, F. Fortunato, L. Golino, M. Marchese, G. Esposito, et al. Exercise training and beta-blocker treatment ameliorate age-dependent impairment of beta-adrenergic receptor signaling and enhance cardiac responsiveness to adrenergic stimulation Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1596 - H1603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. H. Giangrande, J. Zhang, A. Tanner, A. D. Eckhart, R. E. Rempel, E. R. Andrechek, J. M. Layzer, J. R. Keys, P.-O. Hagen, J. R. Nevins, et al. Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia PNAS, August 7, 2007; 104(32): 12988 - 12993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Vroon, C. J. Heijnen, and A. Kavelaars GRKs and arrestins: regulators of migration and inflammation J. Leukoc. Biol., December 1, 2006; 80(6): 1214 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Sanada, J. Yatabe, S. Midorikawa, T. Katoh, S. Hashimoto, T. Watanabe, J. Xu, Y. Luo, X. Wang, C. Zeng, et al. Amelioration of Genetic Hypertension by Suppression of Renal G Protein-Coupled Receptor Kinase Type 4 Expression Hypertension, June 1, 2006; 47(6): 1131 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gros, Q. Ding, J. Chorazyczewski, J. Andrews, J. G. Pickering, R. A. Hegele, and R. D. Feldman The Impact of Blunted beta-Adrenergic Responsiveness on Growth Regulatory Pathways in Hypertension Mol. Pharmacol., January 1, 2006; 69(1): 317 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Keys, R.-H. Zhou, D. M. Harris, C. A. Druckman, and A. D. Eckhart Vascular Smooth Muscle Overexpression of G Protein-Coupled Receptor Kinase 5 Elevates Blood Pressure, Which Segregates With Sex and Is Dependent on Gi-Mediated Signaling Circulation, August 23, 2005; 112(8): 1145 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Gross, J. Tank, M. Obst, R. Plehm, K. J. Blumer, A. Diedrich, J. Jordan, and F. C. Luft Autonomic nervous system and blood pressure regulation in RGS2-deficient mice Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1134 - R1142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Vroon, A. Kavelaars, V. Limmroth, M. S. Lombardi, M. U. Goebel, A.-M. Van Dam, M. G. Caron, M. Schedlowski, and C. J. Heijnen G Protein-Coupled Receptor Kinase 2 in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis J. Immunol., April 1, 2005; 174(7): 4400 - 4406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zeng, H. Sanada, H. Watanabe, G. M. Eisner, R. A. Felder, and P. A. Jose Functional genomics of the dopaminergic system in hypertension Physiol Genomics, November 17, 2004; 19(3): 233 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Dinudom, A. B. Fotia, R. J. Lefkowitz, J. A. Young, S. Kumar, and D. I. Cook The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels PNAS, August 10, 2004; 101(32): 11886 - 11890. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.R. Keys and W.J. Koch The Adrenergic Pathway and Heart Failure Recent Prog. Horm. Res., January 1, 2004; 59(1): 13 - 30. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. Elorza, P. Penela, S. Sarnago, and F. Mayor Jr. MAPK-dependent Degradation of G Protein-coupled Receptor Kinase 2 J. Biol. Chem., August 1, 2003; 278(31): 29164 - 29173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Leosco, G. Iaccarino, E. Cipolletta, D. De Santis, E. Pisani, V. Trimarco, N. Ferrara, P. Abete, D. Sorriento, F. Rengo, et al. Exercise restores {beta}-adrenergic vasorelaxation in aged rat carotid arteries Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H369 - H374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Kohout and R. J. Lefkowitz Regulation of G Protein-Coupled Receptor Kinases and Arrestins During Receptor Desensitization Mol. Pharmacol., January 1, 2003; 63(1): 9 - 18. [Full Text] [PDF]
|
|
|
|
|
|
J. R. Keys, E. A. Greene, W. J. Koch, and A. D. Eckhart Gq-Coupled Receptor Agonists Mediate Cardiac Hypertrophy Via the Vasculature Hypertension, November 1, 2002; 40(5): 660 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Feldman Deactivation of Vasodilator Responses by GRK2 Overexpression: A Mechanism or the Mechanism for Hypertension? Mol. Pharmacol., April 1, 2002; 61(4): 707 - 709. [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
