Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}-catenin signaling.
Mutations in the plakoglobin (JUP) gene have been identified in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. However, the mechanisms underlying plakoglobin dysfunction involved in the pathogenesis of ARVC remain poorly understood. Plakoglobin is a component of both desmosomes and adherens junctions located at the intercalated disc (ICD) of cardiomyocytes, where it functions to link cadherins to the cytoskeleton. In addition, plakoglobin functions as a signaling protein via its ability to modulate the Wnt/β-catenin signaling pathway. To investigate the role of plakoglobin in ARVC, we generated an inducible cardiorestricted knockout (CKO) of the plakoglobin gene in mice. Plakoglobin CKO mice exhibited progressive loss of cardiac myocytes, extensive inflammatory infiltration, fibrous tissue replacement, and cardiac dysfunction similar to those of ARVC patients. Desmosomal proteins from the ICD were decreased, consistent with altered desmosome ultrastructure in plakoglobin CKO hearts. Despite gap junction remodeling, plakoglobin CKO hearts were refractory to induced arrhythmias. Ablation of plakoglobin caused increase β-catenin stabilization associated with activated AKT and inhibition of glycogen synthase kinase 3β. Finally, β-catenin/TCF transcriptional activity may contribute to the cardiac hypertrophy response in plakoglobin CKO mice. This novel model of ARVC demonstrates for the first time how plakoglobin affects β-catenin activity in the heart and its implications for disease pathogenesis.
Center for Translational Medicine, Department of Medicine, Rm. 309, College Bldg., 1025 Walnut St., Philadelphia, PA 19107, USA.
Jifen
J
Li
David
D
Swope
Natalia
N
Raess
Lan
L
Cheng
Eliane J
EJ
Muller
Glenn L
GL
Radice
D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000276:immunology; D003896:Desmosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D051185:gamma Catenin / Q000235:genetics* / Q000378:metabolism
D016207:Cytokines; D051176:beta Catenin; D051185:gamma Catenin
J Cell Biol. 2009 Jul 27;186(2):219-28
19620634
Circulation. 2006 Oct 24;114(17):1799-806
17030684
Circ Res. 2001 Jul 6;89(1):20-5
11440973
Cell. 2005 Dec 2;123(5):903-15
16325583
Lancet. 2009 Apr 11;373(9671):1289-300
19362677
Eur Heart J. 2006 Aug;27(15):1847-54
16774985
J Mol Cell Cardiol. 2008 Mar;44(3):597-606
18201716
N Engl J Med. 2009 Mar 12;360(11):1075-84
19279339
J Biol Chem. 2007 Apr 13;282(15):11221-9
17287208
Nat Genet. 2000 Jun;25(2):139-40
10835623
Circ Res. 2006 Sep 15;99(6):646-55
16917092
Mol Cell Biol. 2000 Jun;20(12):4238-52
10825188
J Clin Invest. 2005 Mar;115(3):527-37
15765134
Circulation. 2010 Apr 6;121(13):1533-41
20172911
Oncogene. 2004 Jan 29;23(4):964-72
14661054
Annu Rev Med. 2010;61:233-53
20059337
Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H270-6
16936006
Orphanet J Rare Dis. 2007 Nov 14;2:45
18001465
J Biol Chem. 2002 Jan 18;277(3):1884-91
11711551
Circ Res. 2005 Feb 18;96(3):346-54
15662031
Br J Pharmacol. 2008 Mar;153 Suppl 1:S414-27
18246092
Br Heart J. 1986 Oct;56(4):321-6
2945574
Heart Vessels. 1998;13(4):199-208
10442402
Circ Res. 2005 Sep 2;97(5):474-81
16100040
Heart Rhythm. 2004 May;1(1):3-11
15851108
EMBO J. 2006 Jul 26;25(14):3298-309
16871158
Am J Hum Genet. 2007 Nov;81(5):964-73
17924338
Mol Cell Biol. 2006 Jun;26(12):4462-73
16738313
J Cell Biol. 1996 Oct;135(1):215-25
8858175
Circ Cardiovasc Genet. 2009 Oct;2(5):428-35
20031617
Circulation. 2006 Sep 5;114(10):1046-55
16923756
J Clin Invest. 2000 Jan;105(2):161-71
10642594
Circ Res. 2009 Nov 20;105(11):1149-58
19834007
J Exp Med. 2009 Aug 3;206(8):1787-802
19635863
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4610-5
12668767
Cardiovasc Pathol. 2004 Jan-Feb;13(1):26-32
14761782
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14602-7
9405659
Circ Res. 2009 May 8;104(9):1076-84
19359597
J Cell Sci. 2000 Sep;113 ( Pt 18):3127-39
10954412
Dev Biol. 1996 Dec 15;180(2):780-5
8954745
J Mol Cell Cardiol. 2007 Sep;43(3):319-26
17673255
J Biol Chem. 1999 Jun 18;274(25):18017-25
10364252
Heart Rhythm. 2009 Aug;6(8 Suppl):S62-5
19541548
Dev Biol. 2000 Jul 15;223(2):441-8
10882528
Cell Physiol Biochem. 2009;23(4-6):327-34
19471100
Nat Rev Mol Cell Biol. 2000 Dec;1(3):208-16
11252896
Circ Res. 2010 Sep 17;107(6):700-14
20847325
Nature. 1995 Dec 21-28;378(6559):785-9
8524413
EMBO Rep. 2002 Jan;3(1):63-8
11751573
Lancet. 2000 Jun 17;355(9221):2119-24
10902626
J Clin Invest. 2006 Jul;116(7):2012-21
16823493