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Animal Models in Cardiovascular Diseases: New Insights from Conditional Models

  • Chapter
Conditional Mutagenesis: An Approach to Disease Models

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 178))

Abstract

Conditional systems have proven to be efficient and powerful to delineate several aspects of cardiac pathophysiology and diseases. The possibility of addressing a particular time point in animal life is certainly an important breakthrough allowed by conditional strategies with temporal control of either transgene expression or gene modifications. The purpose of this review is to present various mouse models for cardiovascular diseases based on conditional approaches.

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References

  • Alden KJ, Goldspink PH, Ruch SW, Buttrick PM, Garcia J (2002) Enhancement of L-type Ca(2+) current from neonatal mouse ventricular myocytes by constitutively active PKC-beta II. Am J Physiol Cell Physiol 282:C768–C774

    PubMed  CAS  Google Scholar 

  • Babij P, Psaltis G, Song D, Kulik J, Mollova N, Abruzzese RV, Nordstrom JL (2003) “Blue heart”: characterization of a mifepristone-dependent system for conditional gene expression in genetically modified animals. Biochim Biophys Acta 1627:15–25

    PubMed  CAS  Google Scholar 

  • Barandon L, Dufourcq P, Costet P, Moreau C, Allieres C, Daret D, Dos Santos P, Lamaziere JM, Couffinhal T, Duplaa C (2005) Involvement of FrzA/sFRP-1 and the Wnt/frizzled pathway in ischemic preconditioning. Circ Res 96:1299–1306

    Article  PubMed  CAS  Google Scholar 

  • Baron U, Freundlieb S, Gossen M, Bujard H (1995) Co-regulation of two gene activities by tetracycline via a bidirectional promoter. Nucleic Acids Res 23:3605–3606

    Article  PubMed  CAS  Google Scholar 

  • Beggah AT, Escoubet B, Puttini S, Cailmail S, Delage V, Ouvrard-Pascaud A, Bocchi B, Peuchmaur M, Delcayre C, Farman N, Jaisser F (2002) Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisensem RNA of the mineralocorticoid receptor in cardiomyocytes. Proc Natl Acad Sci U S A 99:7160–7165

    Article  PubMed  CAS  Google Scholar 

  • Berger S, Bleich M, Schmid W, Cole TJ, Peters J, Watanabe H, Kriz W, Warth R, Greger R, Schutz G (1998) Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism. Proc Natl Acad Sci U S A 95:9424–9429

    Article  PubMed  CAS  Google Scholar 

  • Bernal-Mizrachi C, Gates AC, Weng S, Imamura T, Knutsen RH, DeSantis P, Coleman T, Townsend RR, Muglia LJ, Semenkovich CF (2005) Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature 435:502–506

    Article  PubMed  CAS  Google Scholar 

  • Bo J, Yu W, Zhang YM, Demayo FJ, Wei L (2005) Cardiac-specific and ligand-inducible target gene expression in transgenic mice. J Mol Cell Cardiol 38:685–691

    Article  PubMed  CAS  Google Scholar 

  • Bockamp E, Maringer M, Spangenberg C, Fees S, Fraser S, Eshkind L, Oesch F, Zabel B (2002) Of mice and models: improved animal models for biomedical research. Physiol Genomics 11:115–132

    PubMed  CAS  Google Scholar 

  • Brilla CG, Weber KT (1992) Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 120:893–901

    PubMed  CAS  Google Scholar 

  • Burcin MM, Schiedner G, Kochanek S, Tsai SY, O’Malley BW (1999) Adenovirus-mediated regulable target gene expression in vivo. Proc Natl Acad Sci U S A 96:355–360

    Article  PubMed  CAS  Google Scholar 

  • Czubryt MP, McAnally J, Fishman GI, Olson EN (2003) Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and mitochondrial function by MEF2 and HDAC5. Proc Natl Acad Sci U S A 100:1711–1716

    Article  PubMed  CAS  Google Scholar 

  • Delcayre C, Silvestre JS (1999) Aldosterone and the heart: towards a physiological function? Cardiovasc Res 43:7–12

    Article  PubMed  CAS  Google Scholar 

  • Dor Y, Camenisch TD, Itin A, Fishman GI, McDonald JA Carmeliet, P, Keshet E (2001) A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects. Development 128:1531–1538

    PubMed  CAS  Google Scholar 

  • Dor Y, Djonov V, Abramovitch R, Itin A, Fishman GI, Carmeliet P, Goelman G, Keshet E (2002) Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 21:1939–1947

    Article  PubMed  CAS  Google Scholar 

  • Fishman GI, Kaplan ML, Buttrick PM (1994) Tetracycline-regulated cardiac gene expression in vivo. J Clin Invest 93:1864–1868

    PubMed  CAS  Google Scholar 

  • Furth PA, St Onge L, Boger H, Gruss P, Gossen M, Kistner A, Bujard H, Hennighausen L (1994) Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci U S A 91:9302–9306

    Article  PubMed  CAS  Google Scholar 

  • Gao MH, Bayat H, Roth DM, Yao Zhou J, Drumm J, Burhan J, Hammond HK (2002) Controlled expression of cardiac-directed adenylylcyclase type VI provides increased contractile function. Cardiovasc Res 56:197–204

    Article  PubMed  CAS  Google Scholar 

  • Gros R, Afroze T, You XM, Kabir G Van Wert, R, Kalair W, Hoque AE, Mungrue IN, Husain M (2003) Plasma membrane calcium ATPase overexpression in arterial smooth muscle increases vasomotor responsiveness and blood pressure. Circ Res 93:614–621

    Article  PubMed  CAS  Google Scholar 

  • Gutstein DE, Morley GE, Vaidya D, Liu F, Chen FL, Stuhlmann H, Fishman GI (2001) Heterogeneous expression of Gap junction channels in the heart leads to conduction defects and ventricular dysfunction. Circulation 104:1194–1199

    PubMed  CAS  Google Scholar 

  • Heger J, Godecke A, Flogel U, Merx MW, Molojavyi A, Kuhn-Velten WN, Schrader J (2002) Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. Circ Res 90:93–99

    Article  PubMed  CAS  Google Scholar 

  • Heine HL, Leong HS, Rossi FM, McManus BM, Podor TJ (2005) Strategies of conditional gene expression in myocardium: an overview. Methods Mol Med 112:109–154

    PubMed  CAS  Google Scholar 

  • Ito K, Yan X, Feng X, Manning WJ, Dillmann WH, Lorell BH (2001) Transgenic expression of sarcoplasmic reticulum Ca(2+) ATPase modifies the transition from hypertrophy to early heart failure. Circ Res 89:422–429

    PubMed  CAS  Google Scholar 

  • Jones N, Voskas D, Master Z, Sarao R, Jones J, Dumont DJ (2001) Rescue of the early vascular defects in Tek/Tie2 null mice reveals an essential survival function. EMBO Rep 2:438–445

    PubMed  CAS  Google Scholar 

  • Ju H, Gros R, You X, Tsang S, Husain M, Rabinovitch M (2001) Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice. Proc Natl Acad Sci U S A 98:7469–7474

    Article  PubMed  CAS  Google Scholar 

  • Kistner A, Gossen M, Zimmermann F, Jerecic J, Ullmer C, Lubbert H, Bujard H (1996) Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci U S A 93:10933–10938

    Article  PubMed  CAS  Google Scholar 

  • Kostetskii I, Li J, Xiong Y, Zhou R, Ferrari VA, Patel VV, Molkentin JD, Radice GL (2005) Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ Res 96:346–354

    Article  PubMed  CAS  Google Scholar 

  • Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR (2003) Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 278:39422–39427

    Article  PubMed  CAS  Google Scholar 

  • Le Menuet D, Isnard R, Bichara M, Viengchareun S, Muffat-Joly M, Walker F, Zennaro MC, Lombes M (2001) Alteration of cardiac and renal functions in transgenic mice overexpressing human mineralocorticoid receptor. J Biol Chem 276:38911–38920

    Article  PubMed  Google Scholar 

  • Li J, Patel VV, Kostetskii I, Xiong Y, Chu AF, Jacobson JT, Yu C, Morley GE, Molkentin JD, Radice GL (2005) Cardiac-specific loss of n-cadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis. Circ Res 97:474–481

    Article  PubMed  CAS  Google Scholar 

  • Lutucuta S, Tsybouleva N, Ishiyama M, Defreitas G, Wei L, Carabello B, Marian AJ (2004) Induction and reversal of cardiac phenotype of human hypertrophic cardiomyopathy mutation cardiac troponin T-Q92 in switch on-switch off bigenic mice. J AmColl Cardiol 44:2221–2230

    CAS  Google Scholar 

  • McCloskey DT, Turnbull L, Swigart PM, Zambon AC, Turcato S, Joho S, Grossman W, Conklin BR, Simpson PC, Baker AJ (2005) Cardiac transgenesis with the tetracycline transactivator changes myocardial function and gene expression. Physiol Genomics 22:118–126

    Article  PubMed  CAS  Google Scholar 

  • Metzger D, Feil R (1999) Engineering the mouse genome by site-specific recombination. Curr Opin Biotechnol 10:470–476

    Article  PubMed  CAS  Google Scholar 

  • Minamino T, Gaussin V, DeMayo FJ, Schneider MD (2001) Inducible gene targeting in postnatal myocardiumby cardiac-specific expression of a hormone-activated Cre fusion protein. Circ Res 88:587–592

    PubMed  CAS  Google Scholar 

  • Most P, Remppis A, Katus HA (2002) Conditional AC type VI expression in the heart: relevant insights into function of inducible target gene expression. Cardiovasc Res 56:181–183

    Article  PubMed  CAS  Google Scholar 

  • Mungrue IN, Gros R, You X, Pirani A, Azad A, Csont T, Schulz R, Butany J, Stewart DJ, Husain M (2002) Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest 109:735–743

    Article  PubMed  CAS  Google Scholar 

  • Mungrue IN, Stewart DJ, Husain M (2003) The Janus faces of iNOS Circ Res 93:e74

    Article  PubMed  CAS  Google Scholar 

  • Ouvrard-Pascaud A, Jaisser F (2003) Pathophysiological role of the mineralocorticoid receptor in heart: analysis of conditional transgenic models. Pflugers Arch 445:477–481

    PubMed  CAS  Google Scholar 

  • Ouvrard-Pascaud A, Sainte-Marie Y, Benitah JP, Perrier R, Soukaseum C, Cat AN, Royer A, Le Quang K, Charpentier F, Demolombe S, Mechta-Grigoriou F, Beggah AT, Maison-Blanche P, Oblin ME, Delcayre C, Fishman GI, Farman N, Escoubet B, Jaisser F (2005) Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation 111:3025–3033

    Article  PubMed  CAS  Google Scholar 

  • Passman RS, Fishman GI (1994) Regulated expression of foreign genes in vivo after germline transfer. J Clin Invest 94:2421–2425

    PubMed  CAS  Google Scholar 

  • Periasamy M, Huke S (2001) SERCA pump level is a critical determinant of Ca(2+) homeostasis and cardiac contractility. J Mol Cell Cardiol 33:1053–1063

    Article  PubMed  CAS  Google Scholar 

  • Petrich BG, Molkentin JD, Wang Y (2003) Temporal activation of c-Jun N-terminal kinase in adult transgenic heart via cre-loxP-mediated DNA recombination. FASEB J 17:749–751

    PubMed  CAS  Google Scholar 

  • Pitt B (2004) Effect of aldosterone blockade in patients with systolic left ventricular dysfunction: implications of the RALES and EPHESUS studies. Mol Cell Endocrinol 217:53–58

    Article  PubMed  CAS  Google Scholar 

  • Rabinovitch M (2004) The mouse through the looking glass: a new door into the pathophysiology of pulmonary hypertension. Circ Res 94:1001–1004

    Article  PubMed  CAS  Google Scholar 

  • Radice GL, Rayburn H, Matsunami H, Knudsen KA, Takeichi M, Hynes RO (1997) Developmental defects in mouse embryos lacking N-cadherin. Dev Biol 181:64–78

    Article  PubMed  CAS  Google Scholar 

  • Redfern CH, Coward P, Degtyarev MY, Lee EK, Kwa AT, Hennighausen L, Bujard H, Fishman GI, Conklin BR (1999) Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice [see comments]. Nat Biotechnol 17:165–169

    Article  PubMed  CAS  Google Scholar 

  • Redfern CH, Degtyarev MY, Kwa AT, Salomonis N, Cotte N, Nanevicz T, Fidelman N, Desai K, Vranizan K, Lee EK, Coward P, Shah N, Warrington JA, Fishman GI, Bernstein D, Baker AJ, Conklin BR (2000) Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy. Proc Natl Acad Sci U S A 97:4826–4831

    Article  PubMed  CAS  Google Scholar 

  • Robbins J (2004) Genetic modification of the heart: exploring necessity and sufficiency in the past 10 years. J Mol Cell Cardiol 36:643–652

    Article  PubMed  CAS  Google Scholar 

  • Rossi G, Boscaro M, Ronconi V, Funder JW (2005) Aldosterone as a cardiovascular risk factor. Trends Endocrinol Metab 16:104–107

    Article  PubMed  CAS  Google Scholar 

  • Sanbe A, Gulick J, Hanks MC, Liang Q, Osinska H, Robbins, J (2003) Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. Circ Res 92:609–616

    Article  PubMed  CAS  Google Scholar 

  • Sarao R, Dumont DJ (1998) Conditional transgene expression in endothelial cells. Transgenic Res 7:421–427

    Article  PubMed  CAS  Google Scholar 

  • Sauer B (1998) Inducible gene targeting in mice using the Cre/lox system. Methods 14:381–392

    Article  PubMed  CAS  Google Scholar 

  • Schlaeger TM, Bartunkova S, Lawitts JA, Teichmann G, Risau W, Deutsch U, Sato TN (1997) Uniform vascular-endothelial-cell-specific gene expression in both embryonic and adult transgenic mice. Proc Natl Acad Sci U S A 94:3058–3063

    Article  PubMed  CAS  Google Scholar 

  • Schonig K, Bujard H (2003) Generating conditional mouse mutants via tetracycline-controlled gene expression. Methods Mol Biol 209:69–104

    PubMed  Google Scholar 

  • Schubert W, Yang XY, Yang TT, Factor SM, Lisanti MP, Molkentin JD, Rincon M, Chow CW (2003) Requirement of transcription factor NFAT in developing atrial myocardium. J Cell Biol 161:861–874

    Article  PubMed  CAS  Google Scholar 

  • Sohal DS, Nghiem M, Crackower MA, Witt SA, Kimball TR, Tymitz KM, Penninger JM, Molkentin JD (2001) Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein. Circ Res 89:20–25

    PubMed  CAS  Google Scholar 

  • Suarez J, Gloss B, Belke DD, Hu Y, Scott B, Dieterle T, Kim YK, Valencik ML, McDonald JA, Dillmann WH (2004) Doxycycline inducible expression of SERCA2a improves calcium handling and reverts cardiac dysfunction in pressure overload-induced cardiac hypertrophy. Am J Physiol Heart Circ Physiol 287:H2164–H2172

    Article  PubMed  CAS  Google Scholar 

  • Sun JF, Phung T, Shiojima I, Felske T, Upalakalin JN, Feng D, Kornaga T, Dor T, Dvorak AM, Walsh K, Benjamin LE (2005) Microvascular patterning is controlled by fine-tuning the Akt signal. Proc Natl Acad Sci U S A 102:128–133

    Article  PubMed  CAS  Google Scholar 

  • Sund M, Hamano Y, Sugimoto H, Sudhakar A, Soubasakos M, Yerramalla U, Benjamin LE, Lawler J, Kieran M, Shah A, Kalluri R (2005) Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. Proc Natl Acad Sci U S A 102:2934–2939

    Article  PubMed  CAS  Google Scholar 

  • Syed F, Odley A, Hahn HS, Brunskill EW, Lynch RA, Marreez Y, Sanbe A, Robbins J, Dorn DW 2nd (2004) Physiological growth synergizes with pathological genes in experimental cardiomyopathy. Circ Res 95:1200–1206

    Article  PubMed  CAS  Google Scholar 

  • Tang T, Gao MH, Roth DM, Guo T, Hammond HK (2004) Adenylyl cyclase type VI corrects cardiac sarcoplasmic reticulum calcium uptake defects in cardiomyopathy. AmJ Physiol Heart Circ Physiol 287:H1906–H1912

    Article  CAS  Google Scholar 

  • Teng PI, Dichiara MR, Komuves LG, Abe K, Quertermous T, Topper JN (2002) Inducible and selective transgene expression in murine vascular endothelium. Physiol Genomics 11:99–107

    PubMed  CAS  Google Scholar 

  • Urlinger S, Baron U, Thellmann M, Hasan MT, Bujard H, Hillen W (2000) Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc Natl Acad Sci U S A 97:7963–7968

    Article  PubMed  CAS  Google Scholar 

  • Valencik ML McDonald JA (2001) Codon optimization markedly improves doxycycline regulated gene expression in the mouse heart. Transgenic Res 10:269–275

    Article  PubMed  CAS  Google Scholar 

  • Verrou C, Zhang Y, Zurn C, Schamel WW, Reth M (1999) Comparison of the tamoxifen regulated chimeric Cre recombinases MerCreMer and CreMer. Biol Chem 380:1435–1438

    Article  PubMed  CAS  Google Scholar 

  • Voskas D, Jones N, Van Slyke P, Sturk C, Chang W, Haninec A, Babichev YO, Tran J, Master Z, Chen S, Ward N, Cruz M, Jones J, Kerbel RS, Jothy S, Dagnino L, Arbiser J, Klement G, Dumont DJ (2005) A cyclosporine-sensitive psoriasis-like disease produced in Tie2 transgenic mice. Am J Pathol 166:843–855

    PubMed  CAS  Google Scholar 

  • Wall DS, Gendron RL, Good WV, Miskiewicz E, Woodland M, Leblanc K, Paradis H (2004) Conditional knockdown of tubedown-1 in endothelial cells leads to neovascular retinopathy. Invest Ophthalmol Vis Sci 45:3704–3712

    Article  PubMed  Google Scholar 

  • West J, Fagan K, Steudel W, Fouty B, Lane K, Harral J, Hoedt-Miller M, Tada Y, Ozimek J, Tuder R, Rodman DM (2004) Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res 94:1109–1114

    Article  PubMed  CAS  Google Scholar 

  • Yang LL, Gros R, Kabir MG, Sadi A, Gotlieb AI, Husain M, Stewart DJ (2004) Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice. Circulation 109:255–261

    Article  PubMed  CAS  Google Scholar 

  • You XM, Mungrue IN, Kalair W, Afroze T, Ravi B, Sadi AM, Gros R, Husain M (2003) Conditional expression of a dominant-negative c-Myb in vascular smooth muscle cells inhibits arterial remodeling after injury. Circ Res 92:314–321

    Article  PubMed  CAS  Google Scholar 

  • Yu Z, Redfern CS, Fishman GI (1996) Conditional transgene expression in the heart. Circ Res 79:691–697

    PubMed  CAS  Google Scholar 

  • Zhang Y, Riesterer C, Ayrall AM, Sablitzky F, Littlewood TD, Reth M (1996) Inducible site-directed recombination in mouse embryonic stem cells. Nucleic Acids Res 24:543–548

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. INSERM U772, College De France, 11 Place Marcelin Berthelot, 75231, Paris Cedex 05, France

    A. Nguyen Din Cat, Y. Sainte-Marie & F. Jaisser

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  1. A. Nguyen Din Cat
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  2. Y. Sainte-Marie
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  3. F. Jaisser
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  1. Interfakultäres Institut für Biochemie (IFIB) Signaltransduktion — transgene Modelle, Universität Tübingen, Hoppe-Seyler-Str. 4, 72076, Tübingen, Germany

    Robert Feil

  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, 67404, Illkirch, France

    Daniel Metzger

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Cat, A.N.D., Sainte-Marie, Y., Jaisser, F. (2007). Animal Models in Cardiovascular Diseases: New Insights from Conditional Models. In: Feil, R., Metzger, D. (eds) Conditional Mutagenesis: An Approach to Disease Models. Handbook of Experimental Pharmacology, vol 178. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-35109-2_16

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