title: Adrenergic stress reveals septal hypertrophy and proteasome impairment in heterozygous Mybpc3-targeted knock-in mice.
abstract: Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric septal hypertrophy and is often caused by mutations in MYBPC3 gene encoding cardiac myosin-binding protein C. In contrast to humans, who are already affected at the heterozygous state, mouse models develop the phenotype mainly at the homozygous state. Evidence from cell culture work suggested that altered proteasome function contributes to the pathogenesis of HCM. Here we tested in two heterozygous Mybpc3-targeted mouse models whether adrenergic stress unmasks a specific cardiac phenotype and proteasome dysfunction. The first model carries a human Mybpc3 mutation (Het-KI), the second is a heterozygous Mybpc3 knock-out (Het-KO). Both models were compared to wild-type (WT) mice. Mice were treated with a combination of isoprenaline and phenylephrine (ISO/PE) or NaCl for 1 week. Whereas ISO/PE induced left ventricular hypertrophy (LVH) with increased posterior wall thickness to a similar extent in all groups, it increased septum thickness only in Het-KI and Het-KO. ISO/PE did not affect the proteasomal chymotrypsin-like activity or β5-subunit protein level in Het-KO or wild-type mice (WT). In contrast, both parameters were markedly lower in Het-KI and negatively correlated with the degree of LVH in Het-KI only. In conclusion, adrenergic stress revealed septal hypertrophy in both heterozygous mouse models of HCM, but proteasome dysfunction only in Het-KI mice, which carry a mutant allele and closely mimic human HCM. This supports the hypothesis that proteasome impairment contributes to the pathophysiology of HCM.
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Schlossarek
authors.forename: Friederike
authors.initials: F
authors.lastname: Schuermann
authors.forename: Birgit
authors.initials: B
authors.lastname: Geertz
authors.forename: Giulia
authors.initials: G
authors.lastname: Mearini
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000483:Alleles; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004452:Echocardiography; D055879:Gene Knock-In Techniques; D018014:Gene Transfer Techniques; D006579:Heterozygote; D059765:Homologous Recombination; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D010656:Phenylephrine / Q000008:administration & dosage / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D013312:Stress, Physiological; D000099163:Myosin Binding Protein C
chemical_list: D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D002352:Carrier Proteins; D007545:Isoproterenol; D010656:Phenylephrine; D046988:Proteasome Endopeptidase Complex; D012965:Sodium Chloride; D000099163:Myosin Binding Protein C
references.citation: Biochim Biophys Acta. 2008 Dec;1782(12):749-63
references.pmid: 18634872
references.citation: Circulation. 2005 Feb 22;111(7):906-12
references.pmid: 15699252
references.citation: Curr Opin Cardiol. 2011 May;26(3):190-5
references.pmid: 21415726
references.citation: Genet Couns. 1997;8(2):107-14
references.pmid: 9219008
references.citation: J Biol Chem. 2010 Feb 19;285(8):5674-82
references.pmid: 20018870
references.citation: Circ Res. 2002 Mar 22;90(5):594-601
references.pmid: 11909824
references.citation: Circulation. 2010 Mar 2;121(8):997-1004
references.pmid: 20159828
references.citation: Cardiovasc Res. 2005 Apr 1;66(1):33-44
references.pmid: 15769446
references.citation: J Mol Cell Cardiol. 2011 Apr;50(4):613-20
references.pmid: 21291890
references.citation: Circulation. 2003 May 6;107(17):2227-32
references.pmid: 12707239
references.citation: Cardiovasc Res. 2008 Feb 1;77(3):452-62
references.pmid: 18032391
references.citation: Circ Res. 1998 Jan 9-23;82(1):130-3
references.pmid: 9440712
references.citation: Cardiovasc Res. 2004 Aug 1;63(2):293-304
references.pmid: 15249187
references.citation: Circulation. 1996 Mar 1;93(5):841-2
references.pmid: 8598070
references.citation: Circulation. 2000 Mar 28;101(12):1396-402
references.pmid: 10736283
references.citation: Cardiovasc Res. 2010 Jan 15;85(2):321-9
references.pmid: 19578073
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16918-23
references.pmid: 17075052
references.citation: Circ Res. 2007 Oct 26;101(9):928-38
references.pmid: 17823372
references.citation: Am J Physiol Heart Circ Physiol. 2000 Mar;278(3):H796-805
references.pmid: 10710348
references.citation: Circulation. 2004 Oct 12;110(15):2102-9
references.pmid: 15466629
references.citation: Circ Res. 2003 Nov 14;93(10):896-906
references.pmid: 14615493
references.citation: Br J Pharmacol. 1999 Jul;127(5):1165-76
references.pmid: 10455263
references.citation: Biophys J. 2001 Aug;81(2):1083-92
references.pmid: 11463649
references.citation: Eur Heart J. 2008 Jan;29(2):270-6
references.pmid: 17916581
references.citation: J Biol Chem. 2011 Feb 18;286(7):5300-10
references.pmid: 21148481
references.citation: J Mol Cell Cardiol. 2010 May;48(5):866-75
references.pmid: 19962384
references.citation: Circ Res. 2010 Feb 19;106(3):463-78
references.pmid: 20167943
references.citation: J Mol Biol. 2008 Dec 26;384(4):896-907
references.pmid: 18929575
references.citation: Int J Biochem Cell Biol. 2003 May;35(5):579-89
references.pmid: 12672451
references.citation: Circ Res. 2005 Nov 25;97(11):1156-63
references.pmid: 16224063
references.citation: Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1677-91
references.pmid: 16987021
references.citation: Circ Res. 2010 Oct 29;107(9):1094-101
references.pmid: 20814020
references.citation: J Clin Invest. 1997 Jul 15;100(2):475-82
references.pmid: 9218526
references.citation: Trends Cell Biol. 2000 Dec;10(12):524-30
references.pmid: 11121744
references.citation: Circulation. 2009 Mar 24;119(11):1473-83
references.pmid: 19273718
references.citation: J Biol Chem. 2011 Mar 25;286(12):9929-34
references.pmid: 21257759
references.citation: J Mol Cell Cardiol. 2004 Oct;37(4):823-35
references.pmid: 15380673
references.citation: Cardiovasc Res. 2010 Jan 15;85(2):357-66
references.pmid: 19850579
references.citation: Cell. 1990 Sep 7;62(5):999-1006
references.pmid: 1975517
references.citation: Cardiovasc Res. 2010 Jan 15;85(2):330-8
references.pmid: 19617224
references.citation: J Cell Biol. 2008 Jun 2;181(5):737-45
references.pmid: 18504300
references.citation: Circ Res. 2011 Jun 24;109(1):86-96
references.pmid: 21700950
references.citation: Genomics. 2008 Jan;91(1):52-60
references.pmid: 18060737
references.citation: EMBO J. 1995 May 1;14(9):1952-60
references.pmid: 7744002
references.citation: Cardiovasc Res. 2010 Jan 15;85(2):253-62
references.pmid: 19696071
references.citation: JAMA. 2002 Mar 13;287(10):1308-20
references.pmid: 11886323
references.citation: Circ Res. 1998 Jan 9-23;82(1):124-9
references.pmid: 9440711
references.citation: J Mol Biol. 2007 Mar 16;367(1):36-41
references.pmid: 17254601
references.citation: Circ Res. 2009 Jul 31;105(3):219-22
references.pmid: 19574547
references.citation: Science. 1996 May 3;272(5262):731-4
references.pmid: 8614836
references.citation: Circ Res. 2011 Mar 18;108(6):743-50
references.pmid: 21415408
references.citation: Neurology. 2006 Jan 24;66(2 Suppl 1):S7-19
references.pmid: 16432150
references.citation: Circ Res. 2009 Jul 31;105(3):239-48
references.pmid: 19590044
references.citation: Circ Res. 1997 Mar;80(3):427-34
references.pmid: 9048664
references.citation: Cardiovasc Res. 2006 Feb 1;69(2):370-80
references.pmid: 16380103
references.citation: J Mol Biol. 1999 Nov 26;294(2):443-56
references.pmid: 10610770
references.citation: Nat Med. 2005 Aug;11(8):837-44
references.pmid: 16025126