Induction of cardiomyocyte apoptosis by anti-cardiac myosin heavy chain antibodies in patients with acute myocardial infarction

Abstract

Autoimmune is involved in the pathogenesis of ventricular remodeling in acute myocardial infarction (AMI). In the present study, we investigated the effect of anti-cardiac myosin heavy chain antibodies (AMHCA) from patients with AMI on rat cardiomyocyte apoptosis. Cardiomyocyte apoptosis was observed and measured by DNA end labeling and Annexin-V/PI double-staining assay. The expression of apoptosis related p53 and Bcl-2 protein and the second messenger calcium were detected respectively by Western blotting, patch clamp and confocal calcium imaging. The results showed that AMHCA was able to induce cardiomyocyte apoptosis in a dose dependent manner. Apoptosis-accelerating nucleoprotein p53 was up-regulated, while apoptosis-inhibiting cytoplasmic protein Bcl-2 was down-regulated. In parallel, cytoplasmic calcium concentration was elevated. There was no effect on L-type calcium currents. It is concluded that AMHCA in patients with AMI as a novel triggering factor can induce cardiomyocyte apoptosis, which contributes to ventricular remodeling.

Keywords

autoantibody / cardiac myosin heavy chain / apoptosis / p53 / Bcl-2 / calcium

References

[1] WebbC.S., BonnemaD.D., AhmedS.H., et al.. Specific temporal profile of matrix metalloproteinase release occurs in patients after myocardial infarction: Relation to left ventricular remodeling. Circulation, 2006, 114(10): 1020-1027

[2] SakamotoH., ParishL.M., HamamotoH., et al.. Effect of reperfusion on left ventricular regional remodeling strains after myocardial infarction. Ann Thorac Surg, 2007, 84(5): 1528-1536

[3] MollerJ.E., Torp-PedersenC., KoberL.V.. Is heart failure the critical warning sign for death following myocardial infarction?. Eur Heart J, 2008, 29(7): 833-834

[4] SpencerF.A., MeyerT.E., GoldbergR.J., et al.. Twenty year trends (1975–1995) in the incidence, in-hospital and long-term death rates associated with heart failure complicating acute myocardial infarction. A community-wide perspective. J Am Coll Cardiol, 1999, 34(5): 1378-1387

[5] WedelH., McMurrayJ.J.V., LindbergM., et al.. Predictors of fatal and non-fatal outcomes in the controlled rosuvastatin multinational trial in heart failure (CORONA): Incremental value of apolipoprotein A-1, high-sens itivity C-reactive peptide and N-terminal pro B-type natriuretic peptide. Eur J Heart Fail, 2009, 11(3): 281-291

[6] MaronB.A., LeopoldJ.A.. Aldosterone receptor antagonists: Effective but often forgotten. Circulation, 2010, 121(7): 934-939

[7] ShafiqM.M., MillerA.B., et al.. Blocking aldosterone in heart failure. Ther Adv Cardiovasc Dis, 2009, 3(5): 379-385

[8] OlindeK.D., O’ConnellJ.B.. Inflammatory heart disease: pathogenesis, clinical manifestations, and treatment of myocarditis. Annu Rev Med, 1994, 45(1): 481-490

[9] TowbinJ.A., BowlesK.R., BowlesN.E., et al.. Etiologies of cardiomyopathy and heart failure. Nat Med, 1999, 5(3): 266-267

[10] FeldmanA.M., McNamaraD.M.. Myocarditis. N Engl J Med, 2000, 343(19): 1388-1398

[11] HuangK., HuangD., FuS., et al.. Abnormal calcium “Sparks” in cardiomyocytes of post-myocardial infarction heart. J Huazhong Univ Sci Technol [Med Sci], 2008, 28(4): 401-408

[12] JosephP., MuchnokT.K., KlishisM.L., et al.. Cadmium-induced cell transformation and tumorigenesis are associated with transcriptional activation of c-fos, c-jun, and c-myc proto-oncogenes: Role of cellular calcium and reactive oxygen species. Toxicol Sci, 2001, 61(2): 295-303

[13] CaforioA.L., TonaF., BottaroS., et al.. Clinical implications of anti-heart autoantibodies in myocarditis and dilated cardiomyopathy. Autoimmunity, 2008, 41(1): 35-45

[14] CaforioA.L., MahonN.J., TonaF., et al.. Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: Pathogenetic and clinical significance. Eur J Heart Fail, 2002, 4(4): 411-417

[15] DörnerA., Kallwellis-OparaA., PauschingerM., et al.. Cardiac autoantibodies in viral myocarditis. Heart Fail Clin, 2005, 1(3): 333-343

[16] WarraichR.S., GriffithsE., FalconarA., et al.. Human cardiac myosin autoantibodies impair myocyte contractility: a cause-and-effect relationship. FASEB, 2006, 20(6): 651-660

[17] PangH., LiaoY., WangZ., et al.. Effect of anti-cardiac myosin antibody on prognosis of patients with acute myocardial infarction. J Tongji Med Univ, 2000, 20(1): 46-48

[18] LagerJ., BouvagnetP., PauB., et al.. Levels of ventricular myosin fragments in human sera after myocardial infarction, determined with monoclonal antibodies to myosin heavy chains. Eur J Clin Invest, 1985, 15(6): 422-429

[19] KaniaG., BlyszczukP., ValapertiA., et al.. Prominin-1+/CD133+ bone marrow-derived heart-resident cells suppress experimental autoimmune myocarditis. Cardiovasc Res, 2008, 80(2): 236-245

[20] CaforioA.L.P., MahonN.J., McKennaW.J., et al.. Cardiac autoantibodies to myosin and other heart-specific autoantigens in myocarditis and dilated cardiomyopathy. Autoimmunity, 2001, 34(3): 199-204

[21] MobiniR., MaschkeH., WaagsteinF., et al.. New insights into the pathogenesis of dilated cardiomyopathy: possible underlying autoimmune mechanisms and therapy. Autoimmun Rev, 2004, 3(4): 277-284

[22] LiaoL., SindhwaniR., RojkindM., et al.. Antibody-mediated autoimmune myocarditis depends on genetically determined target organ sensitivity. J Exp Med, 1995, 181(3): 1123-1131

[23] KuanA.P., ChamberlainW., LieuH.D., et al.. Genetic control of autoimmune myocarditis mediated by myosin-specific antibodies. Immunogenetics, 1999, 49(2): 79-85

[24] KuanA.P., ZuckierL., LiaoL., et al.. Immunoglobulin isotype determines pathogenicity in antibody-mediated myocarditis in naive mice. Circ Res, 2000, 86(3): 281-285

[25] NeumannD.A., LaneJ.R., WulffS.M., et al.. In vivo deposition of myosin-specific autoantibodies in the hearts of mice with experimental autoimmune myocarditis. J Immunol, 1992, 148(12): 3806-3813

[26] LiY., HeuserJ.S., CunninghamL.C., et al.. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J Immunol, 2006, 177(11): 8234-8240

[27] KajsturaJ., ChengW., ReissK., et al.. Apoptotic and necrotic myocyte cell death are independent contributing variables of infarct size in rats. Lab Invest, 1996, 74(1): 86-107

[28] Zorc-PleskovičP., AlibegovićA., ZorcM., et al.. Apoptosis of cardiomyocytes in myocarditis. Folia Biol (Praha), 2006, 52(1–2): 6-9

[29] AbbateA., Biondi-ZoccaiG., PetroliniA., et al.. Clinical relevance of apoptosis in early and late post-infarction left ventricular remodeling. Ital Heart J, 2002, 3(12): 699-705

[30] DharapS.S., ChandnaP., WangY., et al.. Molecular targeting of BCL2 and BCLXL proteins by synthetic BCL2 homology 3 domain peptide enhances the efficacy of chemotherapy. J Pharmacol Exp Ther, 2006, 316(3): 992-998

[31] MollU.M., WolffS., SpeidelD., et al.. Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol, 2005, 17(6): 631-636

[32] LoganI.R., McNeillH.V., CookS., et al.. Heat shock factor-1 modulates p53 activity in the transcriptional response to DNA damage. Nucleic Acids Res, 2009, 37(9): 2962-2973

[33] ZhengQ.H., MaL.W., ZhuW.G., et al.. p21Waf1/Cip1 plays a critical role in modulating senescence through changes of DNA methylation. J Cell Biochem, 2006, 98(5): 1230-1248

[34] ZhanQ., CarrierF., FornaceA.J., et al.. Induction of cellular p53 activity by DNA-damaging agents and growth arrest. Mol Cell Biol, 1993, 13(7): 4242-4250

[35] StellerH.. Mechanisms and genes of cellular suicide. Science, 1995, 267(5203): 1445-1449

[36] TakemuraG., OhnoM., FujiwaraH., et al.. Ischemic heart disease and apoptosis. Rinsho Byori, 1997, 45(7): 606-613

[37] BartlingB., HolJ., DarmerD., et al.. Contribution of myocyte apoptosis to myocardial infarction. Basic Res Cardiol, 1998, 93(2): 71-84

[38] ChengE.H.Y., KirschD.G., ClemR. J., et al.. Conversion of Bcl-2 to a bax-like death effector by caspases. Science, 1997, 278(5345): 1966-1968

[39] WuC.F., BishopricN.H., PrattR.E., et al.. Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem, 1997, 272(23): 14 860-14 866