Myocardial extra-cellular matrix and its regulation by metalloproteinases and their inhibitors

Zamaneh Kassiri; Rama Khokha

doi:10.1160/TH04-08-0522

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 93(02): 212-219
DOI: 10.1160/TH04-08-0522

Theme Issue Article

Schattauer GmbH

Myocardial extra-cellular matrix and its regulation by metalloproteinases and their inhibitors

Zamaneh Kassiri

¹Ontario Cancer Institute, University of Toronto, University Health Network, Toronto, Ontario, Canada

,

Rama Khokha

¹Ontario Cancer Institute, University of Toronto, University Health Network, Toronto, Ontario, Canada

› Institutsangaben

Abstract

Summary

Cardiovascular disease poses a major health care burden in the Western world. Following myocardial injuries, ventricular remodelling and dysfunction ensue, which can eventually culminate in heart failure. An important event in left ventricular (LV) remodelling is alteration of the extracellular matrix (ECM) integrity, the structural network that interconnects the myocardial components. The critical role of ECM remodelling in cardiac dilation and heart failure was recognized more than a decade ago, and the molecular factors responsible for this process are now being explored. Abnormal ECM turnover is primarily brought about by an imbalance in the activity of matrix metalloproteinases (MMPs) that degrade ECM components, and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Here we provide an overview of composition of the cardiac ECM, and alterations in ECM regulatory proteins, MMPs and TIMPs, in human heart disease. We also discuss the role of TIMPs, MMPs, and a disintegrin and metalloproteinase (ADAMs) enzymes in cardiac development and function as learned through genetically altered mouse models.

Keywords

Extracellular matrix - metalloproteinases - tissue inhibitor of metalloproteinases - heart disease - genetic mouse models

Volltext

Referenzen

References
1 Weber KT. et al Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms.. J Mol Cell Cardiol 1994; 26: 279-92.
2 Couchman JR. Syndecans: proteoglycan regulators of cell-surface microdomains?. Nat Rev Mol Cell Biol 2003; 4: 926-37.
3 Kim CW. et al Members of the syndecan family of heparan sulfate proteoglycans are expressed in distinct cell-, tissue-, and development-specific patterns.. Mol Biol Cell 1994; 5: 797-805.
4 VanWinkle WB. et al Localization of the transmembrane proteoglycan syndecan-4 and its regulatory kinases in costameres of rat cardiomyocytes: a deconvolution microscopic study.. Anat Rec 2002; 268: 38-46.
5 Debelle L, Tamburro AM. Elastin: molecular description and function.. Int J Biochem Cell Biol 1999; 31: 261-72.
6 Jacob MP. Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions.. Biomed Pharmacother 2003; 57: 195-202.
7 Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly.. Circ Res 2002; 90: 251-62.
8 Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry.. Circ Res 2003; 92: 827-3.
9 Burgess ML. et al Integrin-mediated collagen gel contraction by cardiac fibroblasts. Effects of angiotensin II.. Circ Res 1994; 74: 291-8.
10 Carver W. et al Role of the alpha 1 beta 1 integrin complex in collagen gel contraction in vitro by fibroblasts.. J Cell Physiol 1995; 165: 425-37.
11 van der Flier A, Kuikman I, Baudoin C. et al A novel beta 1 integrin isoform produced by alternative splicing: unique expression in cardiac and skeletal muscle.. FEBS Lett 1995; 369: 340-4.
12 Zhidkova NI. et al Novel isoform of beta 1 integrin expressed in skeletal and cardiac muscle.. Biochem Biophys Res Commun 1995; 214: 279-85.
13 Simpson DG. et al Regulation of cardiac myocyte protein turnover and myofibrillar structure in vitro by specific directions of stretch.. Circ Res 1999; 85: e59-69.
14 Ross RS. The extracellular connections: the role of integrins in myocardial remodeling.. J Card Fail 2002; 8 (Suppl. 06) Suppl S326-31.
15 Li S. et al Fluid shear stress activation of focal adhesion kinase. Linking to mitogen-activated protein kinases.. J Biol Chem 1997; 272: 30455-62.
16 Schlaepfer DD, Hauck CR, Sieg DJ. Signaling through focal adhesion kinase.. Prog Biophys Mol Biol 1999; 71: 435-78.
17 Pham CG. et al Striated muscle-specific beta(1D)-integrin and FAK are involved in cardiac myocyte hypertrophic response pathway.. Am J Physiol Heart Circ Physiol 2000; 279: H2916-26.
18 Franchini KG. et al Early activation of the multicomponent signaling complex associated with focal adhesion kinase induced by pressure overload in the rat heart.. Circ Res 2000; 87: 558-65.
19 Swynghedauw B. Molecular mechanisms of myocardial remodeling.. Physiol Rev 1999; 79: 215-62.
20 Brilla CG, Rupp H. Myocardial collagen matrix remodeling and congestive heart failure.. Cardiologia 1994; 39 (12) (Suppl. 01) 389-93.
21 Gunja-Smith Z. et al Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy. Role of metalloproteinases and pyridinoline cross-links.. Am J Pathol 1996; 148: 1639-48.
22 Feldman AM, Li YY, McTiernan CF. Matrix metalloproteinases in pathophysiology and treatment of heart failure.. Lancet 2001; 357: 654-5.
23 Bonnin CM, Sparrow MP, Taylor RR. Collagen synthesis and content in right ventricular hypertrophy in the dog.. Am J Physiol 1981; 241: H708-13.
24 Weber KT. et al Remodeling and reparation of the cardiovascular system.. J Am Coll Cardiol 1992; 20: 3-16.
25 Siwik DA, Colucci WS. Regulation of matrix metalloproteinases by cytokines and reactive oxygen/ nitrogen species in the myocardium.. Heart Fail Rev 2004; 9: 43-51.
26 Li YY, McTiernan CF, Feldman AM. Proinflammatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells.. Cardiovasc Res 1999; 42: 162-72.
27 Siwik DA. et al Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro.. Circ Res 2000; 86: 1259-65.
28 Giroir BP. et al Inhibition of tumor necrosis factor prevents myocardial dysfunction during burn shock.. Am J Physiol 1994; 267: H118-24.
29 Kapadia S, Lee J, Torre-Amione G. et al Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration.. J Clin Invest 1995; 96: 1042-52.
30 Kapadia SR, Oral H, Lee J. et al Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium.. Circ Res 1997; 81: 187-95.
31 Fine A, Poliks CF, Donahue LP. et al The differential effect of prostaglandin E2 on transforming growth factor-beta and insulin-induced collagen formation in lung fibroblasts.. J Biol Chem 1989; 264: 16988-91.
32 Raghow R, Postlethwaite AE, Keski-Oja J. et al Transforming growth factor-beta increases steady state levels of type I procollagen and fibronectin messenger RNAs posttranscriptionally in cultured human dermal fibroblasts.. J Clin Invest 1987; 79: 1285-8.
33 Edwards DR. et al Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor.. Embo J 1987; 6: 1899-904.
34 Schiemann WP. et al Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades.. J Biol Chem 2002; 277: 27367-77.
35 Hojilla CV. et al Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development.. Br J Cancer 2003; 89: 1817-21.
36 Folgueras AR. et al Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies.. Int J Dev Biol 2004; 48: 411-24.
37 Puente XS, Sanchez LM, Overall CM. et al Human and mouse proteases: a comparative genomic approach.. Nat Rev Genet 2003; 4: 544-58.
38 Seals DF, Courtneidge SA. The ADAMs family of metalloproteases: multidomain proteins with multiple functions.. Genes Dev 2003; 17: 7-30.
39 Fishman DA. et al Membrane-type matrix metalloproteinase expression and matrix metalloproteinase- 2 activation in primary human ovarian epithelial carcinoma cells.. Invasion Metastasis 1996; 16: 150-9.
40 Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity.. Nat Rev Immunol 2004; 4: 617-29.
41 Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression.. Nat Rev Cancer 2002; 2: 161-74.
42 Mann DL, Spinale FG. Activation of matrix metalloproteinases in the failing human heart: breaking the tie that binds.. Circulation 1998; 98: 1699-702.
43 Pei D, Weiss SJ. Transmembrane-deletion mutants of the membrane-type matrix metalloproteinase-1 process progelatinase A and express intrinsic matrixdegrading activity.. J Biol Chem 1996; 271: 9135-40.
44 Holmbeck K, Bianco P, Birkedal-Hansen H. MT1-mmp: a collagenase essential for tumor cell invasive growth.. Cancer Cell 2003; 4: 83-4.
45 Chapman RE, Spinale FG. Extracellular protease activation and unraveling of the myocardial interstitium: critical steps toward clinical applications.. Am J Physiol Heart Circ Physiol 2004; 286: H1-H10.
46 Steffensen B. et al Extracellular matrix binding properties of recombinant fibronectin type II-like modules of human 72-kDa gelatinase/type IV collagenase. High affinity binding to native type I collagen but not native type IV collagen.. J Biol Chem 1995; 270: 11555-66.
47 Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior.. Annu Rev Cell Dev Biol 2001; 17: 463-516.
48 Vincenti MP, Coon CI, Mengshol JA. et al Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1).. Biochem J 1998; 331: 341-6.
49 Nuttall RK. et al Expression analysis of the entire MMP and TIMP gene families during mouse tissue development.. FEBS Lett 2004; 563: 129-34.
50 Brooks PC. et al Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin α v β 3.. Cell 1996; 85: 683-93.
51 Yu Q, Stamenkovic I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion.. Genes Dev 1999; 13: 35-48.
52 Chapman RE. et al Matrix metalloproteinase abundance in human myocardial fibroblasts: effects of sustained pharmacologic matrix metalloproteinase inhibition.. J Mol Cell Cardiol 2003; 35: 539-48.
53 Coker ML. et al Matrix metalloproteinase synthesis and expression in isolated LV myocyte preparations.. Am J Physiol 1999; 277: H777-87.
54 Wang W, Schulze CJ, Suarez-Pinzon WL. et al Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury.. Circulation 2002; 106: 1543-9.
55 Lum L, Reid MS, Blobel CP. Intracellular maturation of the mouse metalloprotease disintegrin MDC15.. J Biol Chem 1998; 273: 26236-47.
56 Roghani M, Becherer JD, Moss ML. et al Metalloprotease- disintegrin MDC9: intracellular maturation and catalytic activity.. J Biol Chem 1999; 274: 3531-40.
57 Hougaard S. et al Trafficking of human ADAM 12-L: retention in the trans-Golgi network.. Biochem Biophys Res Commun 2000; 275: 261-7.
58 Peschon JJ, Slack JL, Reddy P. et al An essential role for ectodomain shedding in mammalian development.. Science 1998; 282: 1281-4.
59 Werb Z, Yan Y. A cellular striptease act.. Science 1998; 282: 1279-80.
60 Black RA, Rauch CT, Kozlosky CJ. et al A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.. Nature 1997; 385: 729-33.
61 Reddy P. et al Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme.. J Biol Chem 2000; 275: 14608-14.
62 Perrella MA. et al Regulation of heparin-binding epidermal growth factor-like growth factor mRNA levels by hypertrophic stimuli in neonatal and adult rat cardiac myocytes.. J Biol Chem 1994; 269: 27045-50.
63 Kubota T, McTiernan CF, Frye CS. et al Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha.. Circ Res 1997; 81: 627-35.
64 Latchman DS. Cardiotrophin-1 (CT-1): a novel hypertrophic and cardioprotective agent.. Int J Exp Pathol 1999; 80: 189-96.
65 Asakura M, Kitakaze M, Takashima S. et al Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy.. Nat Med 2002; 8: 35-40.
66 Yan Y, Shirakabe K, Werb Z. The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors.. J Cell Biol 2002; 158: 221-6.
67 Lee DC. et al TACE/ADAM17 processing of EGFR ligands indicates a role as a physiological convertase.. Ann N Y Acad Sci 2003; 995: 22-38.
68 Killar L, White J, Black R. et al A family of metzincins including TNF-alpha converting enzyme (TACE).. Ann N Y Acad Sci 1999; 878: 442-52.
69 Sahin U, Weskamp G, Kelly K. et al Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands.. J Cell Biol 2004; 164: 769-79.
70 Sottrup-Jensen L, Birkedal-Hansen H. Human fibroblast collagenase-alpha-macroglobulin interactions. Localization of cleavage sites in the bait regions of five mammalian alpha-macroglobulins.. J Biol Chem 1989; 264: 393-401.
71 Mott JD, Thomas CL, Rosenbach MT. et al Posttranslational proteolytic processing of procollagen C-terminal proteinase enhancer releases a metalloproteinase inhibitor.. J Biol Chem 2000; 275: 1384-90.
72 Petitclerc E. et al New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo.. J Biol Chem 2000; 275: 8051-61.
73 Herman MP, Sukhova GK, Kisiel W. et al Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis.. J Clin Invest 2001; 107: 1117-26.
74 Oh J, Takahashi R, Kondo S. et al The membraneanchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis.. Cell 2001; 107: 789-800.
75 Langton KP. et al Localization of the functional domains of human tissue inhibitor of metalloproteinases- 3 and the effects of a Sorsby's fundus dystrophy mutation.. J Biol Chem 1998; 273: 16778-81.
76 Yu WH, Yu S, Meng Q. et al TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix.. J Biol Chem 2000; 275: 31226-32.
77 Murphy G, Willenbrock F. Tissue inhibitors of matrix metalloendopeptidases.. Methods Enzymol 1995; 248: 496-510.
78 Liu YE. et al Preparation and characterization of recombinant tissue inhibitor of metalloproteinase 4 (TIMP-4).. J Biol Chem 1997; 272: 20479-83.
79 Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities.. J Cell Sci 2002; 115: 3719-27.
80 Amour A, Slocombe PM, Webster A. et al TNFalpha converting enzyme (TACE) is inhibited by TIMP-3.. FEBS Lett 1998; 435: 39-44.
81 Kashiwagi M. et al TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5).. J Biol Chem 2001; 276: 12501-4.
82 Amour A, Knight CG, Webster A. et al The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3.. FEBS Lett 2000; 473: 275-9.
83 Tortorella MD. et al Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins.. Science 1999; 284: 1664-6.
84 Young DA, Phillips BW, Lundy C. et al Identification of an initiator-like element essential for the expression of the tissue inhibitor of metalloproteinases-4 (Timp-4) gene.. Biochem J 2002; 364: 89-99.
85 Leco KJ, Apte SS, Taniguchi GT. et al Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues.. FEBS Lett 1997; 401: 213-7.
86 Li YY, Fet al. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart.. Circulation 1998; 98: 1728-34.
87 Tyagi SC. et al Differential gene expression of extracellular matrix components in dilated cardiomyopathy.. J Cell Biochem 1996; 63: 185-98.
88 Altieri P, Brunelli C, Garibaldi S. et al Metalloproteinases 2 and 9 are increased in plasma of patients with heart failure.. Eur J Clin Invest 2003; 33: 648-56.
89 Thomas CV. et al Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy.. Circulation 1998; 97: 1708-15.
90 Spinale FG, Coker ML, Heung LJ. et al A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure.. Circulation 2000; 102: 1944-9.
91 Spinale FG. Matrix metalloproteinases: regulation and dysregulation in the failing heart.. Circ Res 2002; 90: 520-30.
92 Brilla CG, Zhou G, Matsubara L. et al Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone.. J Mol Cell Cardiol 1994; 26: 809-20.
93 Yokoseki O, Yazaki Y, Suzuki J. et al Association of matrix metalloproteinase expression and left ventricular function in idiopathic dilated cardiomyopathy.. Jpn Circ J 2000; 64: 352-7.
94 Noji Y, Shimizu M, Ino H. et al Increased circulating matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction.. Circ J 2004; 68: 355-60.
95 Barton PJ, Birks EJ, Felkin LE. et al Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure.. J Heart Lung Transplant 2003; 22: 738-44.
96 Wang X, Yang L, Qi F. et al Myocardial matrix metalloproteinase-3 and matrix metalloproteinase inhibitor- 1 expression in congestive heart failure.. Zhonghua Nei Ke Za Zhi 2002; 41: 453-5.
97 Timms PM. et al Plasma tissue inhibitor of metalloproteinase- 1 levels are elevated in essential hypertension and related to left ventricular hypertrophy.. Am J Hypertens 2002; 15: 269-72.
98 Lindsay MM. et al TIMP-1: a marker of left ventricular diastolic dysfunction and fibrosis in hypertension.. Hypertension 2002; 40: 136-41.
99 Wilson EM. et al Plasma matrix metalloproteinase and inhibitor profiles in patients with heart failure.. J Card Fail 2002; 8: 390-38.
100 Yamazaki T, Lee JD, Shimizu H. et al Circulating matrix metalloproteinase-2 is elevated in patients with congestive heart failure.. Eur J Heart Fail 2004; 6: 41-5.
101 Roten L. et al 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.
102 Creemers EE, Davis JN, Parkhurst AM. et al Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice.. Am J Physiol Heart Circ Physiol 2003; 284: H364-71.
103 Caterina J. et al Murine TIMP-2 gene-targeted mutation.. Ann N Y Acad Sci 1999; 878: 528-30.
104 Fedak PW. et al TIMP-3 Deficiency leads to dilated cardiomyopathy.. Circulation 2004; 110: 2401-9.
105 Leco KJ, Waterhouse P, Sanchez OH. et al Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3).. J Clin Invest 2001; 108: 817-29.
106 Fata JE, Leco KJ, Voura EB. et al Accelerated apoptosis in the Timp-3-deficient mammary gland.. J Clin Invest 2001; 108: 831-41.
107 Kim HE, Dalal SS, Young E. et al Disruption of the myocardial extracellular matrix leads to cardiac dysfunction.. J Clin Invest 2000; 106: 857-66.
108 Hayashidani S. et al Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction.. Am J Physiol Heart Circ Physiol 2003; 285: H1229-35.
109 Ducharme A. et al Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction.. J Clin Invest 2000; 106: 55-62.
110 Romanic AM, Harrison SM, Bao W. et al Myocardial protection from ischemia/reperfusion injury by targeted deletion of matrix metalloproteinase-9.. Cardiovasc Res 2002; 54: 549-58.
111 Zhou Z, Apte SS, Soininen R. et al Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I.. Proc Natl Acad Sci U S A 2000; 97: 4052-7.
112 Holmbeck K, Bianco P, Caterina J. et al MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.. Cell 1999; 99: 81-92.
113 Weskamp G, Cai H, Brodie TA. et al Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life.. Mol Cell Biol 2002; 22: 1537-44.
114 Kurisaki T, Masuda A, Sudo K. et al Phenotypic analysis of Meltrin alpha (ADAM12)-deficient mice: involvement of Meltrin alpha in adipogenesis and myogenesis.. Mol Cell Biol 2003; 23: 55-61.
115 Iwamoto R, Yamazaki S, Asakura M. et al Heparin- binding EGF-like growth factor and ErbB signaling is essential for heart function.. Proc Natl Acad Sci U S A 2003; 100: 3221-6.
116 Shi W, Chen H, Sun J. et al TACE is required for fetal murine cardiac development and modeling.. Dev Biol 2003; 261: 371-80.
117 Zhao J. et al Pulmonary hypoplasia in mice lacking tumor necrosis factor-alpha converting enzyme indicates an indispensable role for cell surface protein shedding during embryonic lung branching morphogenesis.. Dev Biol 2001; 232: 204-18.
118 Peschon JJ, Torrance DS, Stocking KL. et al TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation.. J Immunol 1998; 160: 943-52.
119 Mann GB. et al Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation.. Cell 1993; 73: 249-61.
120 Luetteke NC, Qiu TH, Peiffer RL. et al TGF alpha deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice.. Cell 1993; 73: 263-78.
121 Chen B, Bronson RT, Klaman LD. et al Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis.. Nat Genet 2000; 24: 296-9.
122 Ozcelik C, Erdmann B, Pilz B. et al Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy.. Proc Natl Acad Sci U S A 2002; 99: 8880-5.
123 Zhou HM, Weskamp G, Chesneau V. et al Essential role for ADAM19 in cardiovascular morphogenesis.. Mol Cell Biol 2004; 24: 96-104.
124 Kurohara K, Komatsu K, Kurisaki T. et al Essential roles of Meltrin beta (ADAM19) in heart development.. Dev Biol 2004; 267: 14-28.