Abstract
Cardiovascular disease has been the leading cause of death worldwide for the last 15 years, accounting for 15 million deaths per year. While interventions are saving more lives, more than 20% of survivors will end up in heart failure. Cell-based and other types of therapy for advanced heart and vascular disease may offer new hope for those afflicted. Although a variety of cell types are under investigation, common issues include cell survival, retention, engraftment, and proliferation. Cardiac extracellular matrix (C-ECM) has compelling features that offer advantages to not only aid cell survival, retention, engraftment, and proliferation but likely has independent therapeutic (paracrine) and mechanical effects. Animal studies and clinical trials are underway to characterize the role of C-ECM and demonstrate efficacy for acute and chronic heart disease. This chapter reviews animal models used to enhance our knowledge of C-ECMs in heart disease and its use in the treatment of heart disease.
Keywords
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Creemers EE, Davis JN, Parkhurst AM, Leenders P, Dowdy KB, Hapke E, Hauet AM, Escobar PG, Cleutjens JP, Smits JF, Daemen MJ, Zile MR, Spinale FG. Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice. Am J Phys Heart Circ Phys. 2003;284:H364–71.
Eskandari MK, Vijungco JD, Flores A, Borensztajn J, Shively V, WH P. Enhanced abdominal aortic aneurysm in TIMP-1-deficient mice. J Surg Res. 2005;123:289–93.
Ikonomidis JS, Hendrick JW, Parkhurst AM, Herron AR, Escobar PG, Dowdy KB, Stroud RE, Hapke E, Zile MR, Spinale FG. Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition. Am J Phys Heart Circ Phys. 2005;288:H149–58.
Roten L, Nemoto S, Simsic J, Coker ML, Rao V, Baicu S, Defreyte G, Soloway PJ, Zile MR, Spinale FG. Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left ventricular geometry and function in mice. J Mol Cell Cardiol. 2000;32:109–20.
Kandalam V, Basu R, Abraham T, Wang X, Soloway PD, Jaworski DM, Oudit GY, Kassiri Z. TIMP2 deficiency accelerates adverse post-myocardial infarction remodeling because of enhanced MT1-MMP activity despite lack of MMP2 activation. Circ Res. 2010;106:796–808.
Kandalam V, Basu R, Moore L, Fan D, Wang X, Jaworski DM, Oudit GY, Kassiri Z. Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress. Circulation. 2011;124:2094–105.
Givvimani S, Kundu S, Narayanan N, Armaghan F, Qipshidze N, Pushpakumar S, Vacek TP, Tyagi SC. TIMP-2 mutant decreases MMP-2 activity and augments pressure overload induced LV dysfunction and heart failure. Arch Physiol Biochem. 2013;119:65–74.
Ramani R, Nilles K, Gibson G, Burkhead B, Mathier M, McNamara D, McTiernan CF. Tissue inhibitor of metalloproteinase-2 gene delivery ameliorates postinfarction cardiac remodeling. Clin Transl Sci. 2011;4:24–31.
Fedak PW, Smookler DS, Kassiri Z, Ohno N, Leco KJ, Verma S, Mickle DA, Watson KL, Hojilla CV, Cruz W, Weisel RD, Li RK, Khokha R. TIMP-3 deficiency leads to dilated cardiomyopathy. Circulation. 2004;110:2401–9.
Kandalam V, Basu R, Abraham T, Wang X, Awad A, Wang W, Lopaschuk GD, Maeda N, Oudit GY, Kassiri Z. Early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction. Am J Phys Heart Circ Phys. 2010;299:H1012–23.
Kassiri Z, Defamie V, Hariri M, Oudit GY, Anthwal S, Dawood F, Liu P, Khokha R. Simultaneous transforming growth factor beta-tumor necrosis factor activation and cross-talk cause aberrant remodeling response and myocardial fibrosis in Timp3-deficient heart. J Biol Chem. 2009;284:29893–904.
Kassiri Z, Oudit GY, Sanchez O, Dawood F, Mohammed FF, Nuttall RK, Edwards DR, Liu PP, Backx PH, Khokha R. Combination of tumor necrosis factor-alpha ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice. Circ Res. 2005;97:380–90.
Tian H, Cimini M, Fedak PW, Altamentova S, Fazel S, Huang ML, Weisel RD, Li RK. TIMP-3 deficiency accelerates cardiac remodeling after myocardial infarction. J Mol Cell Cardiol. 2007;43:733–43.
Takawale A, Zhang P, Azad A, Wang W, Wang X, Murray AG, Kassiri Z. Myocardial overexpression of TIMP3 after myocardial infarction exerts beneficial effects by promoting angiogenesis and suppressing early proteolysis. Am J Phys Heart Circ Phys. 2017;313:H224–36.
Koskivirta I, Kassiri Z, Rahkonen O, Kiviranta R, Oudit GY, McKee TD, Kyto V, Saraste A, Jokinen E, Liu PP, Vuorio E, Khokha R. Mice with tissue inhibitor of metalloproteinases 4 (Timp4) deletion succumb to induced myocardial infarction but not to cardiac pressure overload. J Biol Chem. 2010;285:24487–93.
Yarbrough WM, Baicu C, Mukherjee R, Van Laer A, Rivers WT, McKinney RA, Prescott CB, Stroud RE, Freels PD, Zellars KN, Zile MR, Spinale FG. Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy. Am J Phys Heart Circ Phys. 2014;307:H752–61.
Zavadzkas JA, Stroud RE, Bouges S, Mukherjee R, Jones JR, Patel RK, McDermott PJ, Spinale FG. Targeted overexpression of tissue inhibitor of matrix metalloproteinase-4 modifies post-myocardial infarction remodeling in mice. Circ Res. 2014;114:1435–45.
Ramirez FD, Motazedian P, Jung RG, Di Santo P, MacDonald ZD, Moreland R, Simard T, Clancy AA, Russo JJ, Welch VA, Wells GA, Hibbert B. Methodological rigor in preclinical cardiovascular studies: targets to enhance reproducibility and promote research translation. Circ Res. 2017;120:1916–26.
Borst O, Ochmann C, Schonberger T, Jacoby C, Stellos K, Seizer P, Flogel U, Lang F, Gawaz M. Methods employed for induction and analysis of experimental myocardial infarction in mice. Cellular physiology and biochemistry : international journal of experimental cellular physiology. Biochem Pharmacol. 2011;28:1–12.
Goldman S, Raya TE. Rat infarct model of myocardial infarction and heart failure. J Card Fail. 1995;1:169–77.
Camacho P, Fan H, Liu Z, He JQ. Small mammalian animal models of heart disease. Am J Cardiovasc Dis. 2016;6:70–80.
Barnes J, Pat B, Chen YW, Powell PC, Bradley WE, Zheng J, Karki A, Cui X, Guichard J, Wei CC, Collawn J, Dell'Italia LJ. Whole-genome profiling highlights the molecular complexity underlying eccentric cardiac hypertrophy. Ther Adv Cardiovasc Dis. 2014;8:97–118.
Tarnavski O. Mouse surgical models in cardiovascular research. Methods Mol Biol. 2009;573:115–37.
Hamrell BB, Hultgren PB. Reduced isotonic sarcomere shortening in rabbit right ventricular pressure overload hypertrophy. J Mol Cell Cardiol. 1992;24:133–47.
Kapur NK, Paruchuri V, Aronovitz MJ, Qiao X, Mackey EE, Daly GH, Ughreja K, Levine J, Blanton R, Hill NS, Karas RH. Biventricular remodeling in murine models of right ventricular pressure overload. PLoS One. 2013;8:e70802.
Rain S, Andersen S, Najafi A, Gammelgaard Schultz J, da Silva Goncalves Bos D, Handoko ML, Bogaard HJ, Vonk-Noordegraaf A, Andersen A, van der Velden J, Ottenheijm CA, de Man FS. Right ventricular myocardial stiffness in experimental pulmonary arterial hypertension: relative contribution of fibrosis and myofibril stiffness. Circ Heart Fail. 2016;9:1–9.
Reddy S, Zhao M, Hu DQ, Fajardo G, Katznelson E, Punn R, Spin JM, Chan FP, Bernstein D. Physiologic and molecular characterization of a murine model of right ventricular volume overload. Am J Phys Heart Circ Phys. 2013;304:H1314–27.
Abassi Z, Goltsman I, Karram T, Winaver J, Hoffman A. Aortocaval fistula in rat: a unique model of volume-overload congestive heart failure and cardiac hypertrophy. J Biomed Biotechnol. 2011;2011:729497.
Karram T, Hoffman A, Bishara B, Brodsky S, Golomb E, Winaver J, Abassi Z. Induction of cardiac hypertrophy by a controlled reproducible sutureless aortocaval shunt in the mouse. J Invest Surg. 2005;18:325–34.
Miyamoto T, Takeishi Y, Shishido T, Takahashi H, Itoh M, Kubota I, Tomoike H. Role of nitric oxide in the progression of cardiovascular remodeling induced by carotid arterio-venous shunt in rabbits. Jpn Heart J. 2003;44:127–37.
Borer JS, Truter S, Herrold EM, Falcone DJ, Pena M, Carter JN, Dumlao TF, Lee JA, Supino PG. Myocardial fibrosis in chronic aortic regurgitation: molecular and cellular responses to volume overload. Circulation. 2002;105:1837–42.
Corno AF, Cai X, Jones CB, Mondani G, Boyett MR, Jarvis JC, Hart G. Congestive heart failure: experimental model. Front Pediatr. 2013;1:33.
Nogueira-Ferreira R, Vitorino R, Ferreira R, Henriques-Coelho T. Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: a network approach. Pulm Pharmacol Ther. 2015;35:8–16.
Bai P, Mabley JG, Liaudet L, Virag L, Szabo C, Pacher P. Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity. Oncol Rep. 2004;11:505–8.
Carvalho FS, Burgeiro A, Garcia R, Moreno AJ, Carvalho RA, Oliveira PJ. Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med Res Rev. 2014;34:106–35.
Hayward R, Hydock DS. Doxorubicin cardiotoxicity in the rat: an in vivo characterization. J Am Assoc Lab Anim Sci .: JAALAS. 2007;46:20–32.
Wang JJ, Rau C, Avetisyan R, Ren S, Romay MC, Stolin G, Gong KW, Wang Y, Lusis AJ. Genetic dissection of cardiac remodeling in an isoproterenol-induced heart failure mouse model. PLoS Genet. 2016;12:e1006038.
Carll AP, Willis MS, Lust RM, Costa DL, Farraj AK. Merits of non-invasive rat models of left ventricular heart failure. Cardiovasc Toxicol. 2011;11:91–112.
Wang Z, Schreier DA, Hacker TA, Chesler NC. Progressive right ventricular functional and structural changes in a mouse model of pulmonary arterial hypertension. Physiol Rep. 2013;1:e00184.
Liu A, Philip J, Vinnakota KC, Van den Bergh F, Tabima DM, Hacker T, Beard DA, Chesler NC. Estrogen maintains mitochondrial content and function in the right ventricle of rats with pulmonary hypertension. Physiol Rep. 2017;5:e13157.
Horn MA, Trafford AW. Aging and the cardiac collagen matrix: novel mediators of fibrotic remodelling. J Mol Cell Cardiol. 2016;93:175–85.
Hacker TA, McKiernan SH, Douglas PS, Wanagat J, Aiken JM. Age-related changes in cardiac structure and function in Fischer 344 x Brown Norway hybrid rats. Am J Phys Heart Circ Phys. 2006;290:H304–11.
Shiomi T, Tsutsui H, Ikeuchi M, Matsusaka H, Hayashidani S, Suematsu N, Wen J, Kubota T, Takeshita A. Streptozotocin-induced hyperglycemia exacerbates left ventricular remodeling and failure after experimental myocardial infarction. J Am Coll Cardiol. 2003;42:165–72.
Ouwens DM, Boer C, Fodor M, de Galan P, Heine RJ, Maassen JA, Diamant M. Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia. 2005;48:1229–37.
van Dokkum RP, Eijkelkamp WB, Kluppel AC, Henning RH, van Goor H, Citgez M, Windt WA, van Veldhuisen DJ, de Graeff PA, de Zeeuw D. Myocardial infarction enhances progressive renal damage in an experimental model for cardio-renal interaction. J Am Soc Nephrol. 2004;15:3103–10.
Lu D, Wang K, Wang S, Zhang B, Liu Q, Zhang Q, Geng J, Shan Q. Beneficial effects of renal denervation on cardiac angiogenesis in rats with prolonged pressure overload. Acta Physiol. 2017;220:47–57.
Windt WA, Henning RH, Kluppel AC, Xu Y, de Zeeuw D, van Dokkum RP. Myocardial infarction does not further impair renal damage in 5/6 nephrectomized rats. Nephrol Dial Transplant. 2008;23:3103–10.
Gavras H, Brunner HR, Laragh JH, Vaughan ED Jr, Koss M, Cote LJ, Gavras I. Malignant hypertension resulting from deoxycorticosterone acetate and salt excess: role of renin and sodium in vascular changes. Circ Res. 1975;36:300–9.
O'Brien D, Chunduri P, Iyer A, Brown L. L-carnitine attenuates cardiac remodelling rather than vascular remodelling in deoxycorticosterone acetate-salt hypertensive rats. Basic Clin Pharmacol Toxicol. 2010;106:296–301.
Dixon JA, Spinale FG. Large animal models of heart failure: a critical link in the translation of basic science to clinical practice. Circ Heart Fail. 2009;2:262–71.
Dubi S, Arbel Y. Large animal models for diastolic dysfunction and diastolic heart failure-a review of the literature. Cardiovasc Pathol. 2010;19:147–52.
Power JM, Tonkin AM. Large animal models of heart failure. Aust NZ J Med. 1999;29:395–402.
Yarbrough WM, Spinale FG. Large animal models of congestive heart failure: a critical step in translating basic observations into clinical applications. J Nucl Cardiol. 2003;10:77–86.
Recchia FA, Lionetti V. Animal models of dilated cardiomyopathy for translational research. Vet Res Commun. 2007;31(Suppl 1):35–41.
Jugdutt BI. The dog model of left ventricular remodeling after myocardial infarction. J Card Fail. 2002;8:S472–5.
Wayman NS, McDonald MC, Chatterjee PK, Thiemermann C. Models of coronary artery occlusion and reperfusion for the discovery of novel antiischemic and antiinflammatory drugs for the heart. Methods Mol Biol. 2003;225:199–208.
Schmuck EG, Koch JM, Hacker TA, Hatt CR, Tomkowiak MT, Vigen KK, Hendren N, Leitzke C, Zhao YQ, Li Z, Centanni JM, Hei DJ, Schwahn D, Kim J, Hematti P, Raval AN. Intravenous Followed by X-ray Fused with MRI-Guided Transendocardial Mesenchymal Stem Cell Injection Improves Contractility Reserve in a Swine Model of Myocardial Infarction. J Cardiovasc Transl Res. 2015;8:438–48.
van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van Belle E, Gyongyosi M, Sluijter JP, Cramer MJ, Doevendans PA, Chamuleau SA. Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovasc Res. 2011;91:649–58.
Harper J, Harper E, Covell JW. Collagen characterization in volume-overload- and pressure-overload-induced cardiac hypertrophy in minipigs. Am J Phys. 1993;265:H434–8.
Wittnich C, Belanger MP, Oh BS, Salerno TA. Surgical model of volume overload-induced ventricular myocardial hypertrophy (VHvo) to study a clinical problem in humans. J Invest Surg. 1991;4:333–8.
Kawase Y, Ly HQ, Prunier F, Lebeche D, Shi Y, Jin H, Hadri L, Yoneyama R, Hoshino K, Takewa Y, Sakata S, Peluso R, Zsebo K, Gwathmey JK, Tardif JC, Tanguay JF, Hajjar RJ. Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. J Am Coll Cardiol. 2008;51:1112–9.
Hyldebrandt JA, Siven E, Agger P, Frederiksen CA, Heiberg J, Wemmelund KB, Ravn HB. Effects of milrinone and epinephrine or dopamine on biventricular function and hemodynamics in an animal model with right ventricular failure after pulmonary artery banding. Am J Phys Heart Circ Phys. 2015;309:H206–12.
Lambert V, Capderou A, Le Bret E, Rucker-Martin C, Deroubaix E, Gouadon E, Raymond N, Stos B, Serraf A, Renaud JF. Right ventricular failure secondary to chronic overload in congenital heart disease: an experimental model for therapeutic innovation. J Thorac Cardiovasc Surg. 2010;139:1197–1204, 1204 e1191.
Mazumder R, Schroeder S, Mo X, Clymer BD, White RD, Kolipaka A. In vivo quantification of myocardial stiffness in hypertensive porcine hearts using MR elastography. J Magn Reson Imaging. 2017;45:813–20.
Feld Y, Dubi S, Reisner Y, Schwammenthal E, Shofti R, Pinhasi A, Carasso S, Elami A. Energy transfer from systole to diastole: a novel device-based approach for the treatment of diastolic heart failure. Acute Card Care. 2011;13:232–42.
Li Y, Fuchimoto D, Sudo M, Haruta H, Lin QF, Takayama T, Morita S, Nochi T, Suzuki S, Sembon S, Nakai M, Kojima M, Iwamoto M, Hashimoto M, Yoda S, Kunimoto S, Hiro T, Matsumoto T, Mitsumata M, Sugitani M, Saito S, Hirayama A, Onishi A. Development of Human-Like Advanced Coronary Plaques in Low-Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques. J Am Heart Assoc. 2016;5:e002779.
Wei J, Ouyang H, Wang Y, Pang D, Cong NX, Wang T, Leng B, Li D, Li X, Wu R, Ding Y, Gao F, Deng Y, Liu B, Li Z, Lai L, Feng H, Liu G, Deng X. Characterization of a hypertriglyceridemic transgenic miniature pig model expressing human apolipoprotein CIII. FEBS J. 2012;279:91–9.
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Hacker, T.A. (2018). Animal Models and Cardiac Extracellular Matrix Research. In: Schmuck, E., Hematti, P., Raval, A. (eds) Cardiac Extracellular Matrix. Advances in Experimental Medicine and Biology, vol 1098. Springer, Cham. https://doi.org/10.1007/978-3-319-97421-7_3
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