title: GRK2 as a novel gene therapy target in heart failure.
abstract: Despite significant advances in pharmacological and clinical treatment, heart failure (HF) remains a leading cause of morbidity and mortality worldwide. HF is a chronic and progressive clinical syndrome characterized by a reduction in left ventricular (LV) ejection fraction and adverse remodeling of the myocardium. The past several years have seen remarkable progress using animal models in unraveling the cellular and molecular mechanisms underlying HF pathogenesis and progression. These studies have revealed potentially novel therapeutic targets/strategies. The application of cardiac gene transfer, which allows for the manipulation of targets in cardiomyocytes, appears to be a promising therapeutic tool in HF. β-adrenergic receptor (βAR) dysfunction represents a hallmark abnormality of chronic HF, and increased G protein-coupled receptor kinase 2 (GRK2) levels/activity in failing myocardium is among these alterations. In the past 15years, several animal studies have shown that expression of a peptide inhibitor of GRK2 (βARKct) can improve the contractile function of failing myocardium including promoting reverse remodeling of the LV. Therefore, data support the use of the βARKct as a promising candidate for therapeutic application in human HF. Importantly, recent studies in cardiac-specific GRK2 knockout mice have corroborated GRK2 being pathological in failing myocytes. The purpose of this review is to discuss: 1) the alterations of βAR signaling that occur in HF, 2) the evidence from transgenic mouse studies investigating the impact of GRK2 manipulation in failing myocardium, 3) the therapeutic efficacy of in vivo βARKct gene therapy in HF, and 4) the intriguing possibility of lowering HF-related sympathetic nervous system hyperactivity by inhibiting GRK2 activity in the adrenal gland. This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy".
authors.affiliation: Center for Translational Medicine and George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rengo
authors.forename: Anastasios
authors.initials: A
authors.lastname: Lymperopoulos
authors.forename: Dario
authors.initials: D
authors.lastname: Leosco
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000818:Animals; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000235:genetics / Q000628:therapy*; D006801:Humans; D008954:Models, Biological
chemical_list: D054769:G-Protein-Coupled Receptor Kinase 2
references.citation: J Gene Med. 2005 Sep;7(9):1172-7
references.pmid: 15880449
references.citation: Hypertension. 2002 Jun;39(6):1058-63
references.pmid: 12052842
references.citation: Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50
references.pmid: 12209124
references.citation: Mol Ther. 2008 Feb;16(2):302-7
references.pmid: 18223549
references.citation: Basic Res Cardiol. 2001 Jul;96(4):364-8
references.pmid: 11518192
references.citation: Ann Thorac Surg. 2001 Nov;72(5):1657-61
references.pmid: 11722061
references.citation: J Mol Cell Cardiol. 2003 Oct;35(10):1167-74
references.pmid: 14519424
references.citation: J Clin Invest. 2001 Apr;107(8):967-74
references.pmid: 11306600
references.citation: J Biol Chem. 1997 Jul 4;272(27):17223-9
references.pmid: 9202046
references.citation: Circulation. 1999 Nov 30;100(22):2210-2
references.pmid: 10577992
references.citation: Clin Transl Sci. 2010 Feb;3(1):14-8
references.pmid: 20443948
references.citation: Clin Transl Sci. 2010 Jun;3(3):81-9
references.pmid: 20590676
references.citation: Circulation. 2004 Apr 6;109(13):1590-3
references.pmid: 15051637
references.citation: Circulation. 2004 Jul 20;110(3):330-6
references.pmid: 15249510
references.citation: Nat Med. 2007 Mar;13(3):315-23
references.pmid: 17322894
references.citation: J Am Coll Cardiol. 1993 Oct;22(4 Suppl A):119A-126A
references.pmid: 8397231
references.citation: J Biol Chem. 1993 Nov 15;268(32):23735-8
references.pmid: 8226899
references.citation: J Thorac Cardiovasc Surg. 2004 Mar;127(3):787-93
references.pmid: 15001908
references.citation: Circulation. 2000 Feb 8;101(5):558-69
references.pmid: 10662755
references.citation: Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H2032-8
references.pmid: 20304818
references.citation: N Engl J Med. 1982 Jul 22;307(4):205-11
references.pmid: 6283349
references.citation: Trends Cardiovasc Med. 2007 Oct;17(7):215-21
references.pmid: 17936202
references.citation: J Card Fail. 2006 Jun;12(5):360-8
references.pmid: 16762799
references.citation: Circulation. 1993 Feb;87(2):454-63
references.pmid: 8381058
references.citation: Circulation. 1998 Oct 27;98(17):1783-9
references.pmid: 9788834
references.citation: J Mol Cell Cardiol. 2002 Jun;34(6):669-77
references.pmid: 12054854
references.citation: Circulation. 2002 Feb 26;105(8):904-7
references.pmid: 11864915
references.citation: Pharmacol Ther. 1993 Dec;60(3):405-30
references.pmid: 7915424
references.citation: Nature. 2002 Jan 10;415(6868):206-12
references.pmid: 11805844
references.citation: Circulation. 2009 Jan 6;119(1):89-98
references.pmid: 19103992
references.citation: Proc Natl Acad Sci U S A. 1999 May 25;96(11):6400-5
references.pmid: 10339599
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12457-62
references.pmid: 18711143
references.citation: Mol Endocrinol. 2003 Aug;17(8):1640-6
references.pmid: 12764077
references.citation: Circ Res. 2000 Dec 8;87(12):1172-9
references.pmid: 11110775
references.citation: Circ Res. 2008 Aug 15;103(4):413-22
references.pmid: 18635825
references.citation: Trends Mol Med. 2007 Dec;13(12):503-11
references.pmid: 17981507
references.citation: J Card Fail. 2009 Apr;15(3):171-81
references.pmid: 19327618
references.citation: Gene Ther. 1999 Sep;6(9):1574-83
references.pmid: 10490767
references.citation: Prog Neurobiol. 2002 Feb;66(2):61-79
references.pmid: 11900882
references.citation: Eur Heart J. 2005 Sep;26(17):1752-8
references.pmid: 16055494
references.citation: Annu Rev Pharmacol Toxicol. 1997;37:167-203
references.pmid: 9131251
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7000-5
references.pmid: 9618528
references.citation: Circulation. 2001 Oct 23;104(17):2069-74
references.pmid: 11673348
references.citation: J Biol Chem. 1998 Jul 17;273(29):18180-4
references.pmid: 9660778
references.citation: Circulation. 2007 May 15;115(19):2506-15
references.pmid: 17470693
references.citation: J Clin Invest. 2001 Jan;107(2):191-8
references.pmid: 11160135
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5809-14
references.pmid: 11331748
references.citation: Circ Res. 1996 Sep;79(3):455-60
references.pmid: 8781479
references.citation: Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12100-5
references.pmid: 9342369
references.citation: Annu Rev Physiol. 2004;66:49-75
references.pmid: 14977396
references.citation: Circ Res. 1986 Sep;59(3):297-309
references.pmid: 2876788
references.citation: J Card Fail. 2008 Jun;14(5):355-67
references.pmid: 18514926
references.citation: J Clin Invest. 1997 May 1;99(9):2087-93
references.pmid: 9151780
references.citation: Circulation. 2009 Apr 14;119(14):e391-479
references.pmid: 19324966
references.citation: J Biol Chem. 2010 May 21;285(21):16378-86
references.pmid: 20351116
references.citation: Circulation. 1999 Aug 10;100(6):648-53
references.pmid: 10441103
references.citation: Science. 1995 Jun 2;268(5215):1350-3
references.pmid: 7761854
references.citation: Circ Res. 2008 Jun 20;102(12):1458-70
references.pmid: 18566312
references.citation: Circ Res. 2005 Apr 15;96(7):756-66
references.pmid: 15746443
references.citation: J Clin Invest. 1997 Jan 15;99(2):288-96
references.pmid: 9005997
references.citation: Eur J Pharmacol. 2004 Apr 12;489(3):167-77
references.pmid: 15087239
references.citation: Mol Ther. 2008 Jun;16(6):1073-80
references.pmid: 18414476
references.citation: Circ Res. 2006 Oct 27;99(9):996-1003
references.pmid: 17008600
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1607-12
references.pmid: 11171998
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12974-9
references.pmid: 8917529
references.citation: Circulation. 2001 Mar 6;103(9):1311-6
references.pmid: 11238278
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5428-33
references.pmid: 10779554
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9954-9
references.pmid: 8790438