S100A1 Gene Therapy in Small and Large Animals

  • Patrick MostEmail author
  • Philip Raake
  • Christophe Weber
  • Hugo A. Katus
  • Sven T. Pleger
Part of the Methods in Molecular Biology book series (MIMB, volume 963)


Myocardial in vivo gene delivery is a valuable technique to investigate the relevance of a protein of interest on cardiac contractile function, hypertrophy, and energy state in healthy animals as well as in a variety of models of cardiovascular disease. Rodent models are used to screen effects and to investigate molecular mechanisms, while large animal models, more closely reflecting human anatomy, physiology, and function, are inevitable for translational therapeutic approaches. The gene of interest, whose expression is driven by a non-cardioselective or cardioselective promotor is cloned into a viral vector. This vehicle is then delivered using an appropriate administration route to target the heart and to achieve efficient protein expression in myocardium.

Here we describe myocardial gene therapy in small and large animal models of postischemic heart failure used to reveal the positive inotrope, antihypertrophic, and pro-energetic action of the small calcium sensor protein S100A1.

Key words

S100A1 Calcium EF-hand Myocardial gene therapy Retroinfusion Antegrade ­delivery Adenovirus Adeno-associated virus Efficacy Cardioselective 



This work was supported by NIH grants: R01HL92130 and R01HL92130-02S1 (P.M.); Deutsche Forschungsgemeinschaft: 562/1-1 (P.M. and S.T.P.); and the Bundesministerium für Bildung und Forschung: 01GU0527 (P.M., H.A.K.); the Pennsylvania-Delaware Affiliate of the American Heart Association (S.T.P.); the Lilly-Stipendium of the Deutsche Gesellschaft für Kardiologie (S.T.P.).


  1. 1.
    del Monte F, Hajjar R (2003) Targeting calium cycling proteins in heart failure through gene transfer. J Physiol 546:49–61PubMedCrossRefGoogle Scholar
  2. 2.
    Wehrens XH, Marks AR (2004) Novel therapeutic approaches for heart failure by normalizing calcium cycling. Nat Rev Drug Discov 3:565–573PubMedCrossRefGoogle Scholar
  3. 3.
    Wasala NB, Shin JH, Duan D (2011) The evolution of heart gene delivery vectors. J Gene Med 13:557–565PubMedCrossRefGoogle Scholar
  4. 4.
    Raake PW, Tscheschner H, Reinkober J, Ritterhoff J, Katus HA, Koch WJ, Most P (2011) Gene therapy targets in heart failure: the path to translation. Clin Pharmacol Ther 90:542–553PubMedCrossRefGoogle Scholar
  5. 5.
    Heine HL, Leong HS, Rossi FM, McManus BM, Podor TJ (2005) Strategies of conditional gene expression in myocardium: an overview. Methods Mol Med 112:109–154PubMedCrossRefGoogle Scholar
  6. 6.
    Ishikawa K, Tilemann L, Fish K, Hajjar RJ (2011) Gene delivery methods in cardiac gene therapy. J Gene Med 13:566–572PubMedCrossRefGoogle Scholar
  7. 7.
    Dixon JA, Spinale FG (2009) Large animal models of heart failure: a critical link in the translation of basic science to clinical practice. Circ Heart Fail 2:262–271PubMedCrossRefGoogle Scholar
  8. 8.
    Pleger ST, Boucher M, Most P, Koch WJ (2007) Targeting myocardial beta-adrenergic receptor signaling and calcium cycling for heart failure gene therapy. J Card Fail 13:401–414PubMedCrossRefGoogle Scholar
  9. 9.
    Raake PW, Hinkel R, Müller S, Delker S, Kreuzpointner R, Kupatt C, Katus HA, Kleinschmidt JA, Boekstegers P, Müller OJ (2008) Cardio-specific long-term gene expression in a porcine model after selective pressure-regulated retroinfusion of adeno-associated viral (AAV) vectors. Gene Ther 15:12–17PubMedCrossRefGoogle Scholar
  10. 10.
    Emani SM, Shah AS, Bowman MK, Emani S, Wilson K, Glower DD, Koch WJ (2003) Catheter-based intracoronary myocardial adenoviral gene delivery: importance of intraluminal seal and infusion flow rate. Mol Ther 8:306–313PubMedCrossRefGoogle Scholar
  11. 11.
    Wang J, Faust SM, Rabinowitz JE (2011) The next step in gene delivery: molecular engineering of adeno-associated virus serotypes. J Mol Cell Cardiol 50:793–802PubMedCrossRefGoogle Scholar
  12. 12.
    Raake P, von Degenfeld G, Hinkel R, Vachenauer R, Sandner T, Beller S, Andrees M, Kupatt C, Schuler G, Boekstegers P (2004) Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins: comparison with surgical and percutaneous intramyocardial gene delivery. J Am Coll Cardiol 44:1124–1129PubMedCrossRefGoogle Scholar
  13. 13.
    Pleger ST, Shan C, Ksienzyk J, Bekeredjian R, Boekstegers P, Hinkel R, Schinkel S, Leuchs B, Ludwig J, Qiu G, Weber C, Raake P, Koch WJ, Katus HA, Müller OJ, Most P (2011) Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model. Sci Transl Med 20:92ra64CrossRefGoogle Scholar
  14. 14.
    Pleger ST, Most P, Boucher M, Soltys S, Chuprun JK, Pleger W, Gao E, Dasgupta A, Rengo G, Remppis A, Katus HA, Eckhart AD, Rabinowitz JE, Koch WJ (2007) Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue. Circulation 115:2506–2515PubMedCrossRefGoogle Scholar
  15. 15.
    Kraus C, Rohde D, Weidenhammer C, Qiu G, Pleger ST, Voelkers M, Boerries M, Remppis A, Katus HA, Most P (2009) S100A1 in ­cardiovascular health and disease: closing the gap between basic science and clinical therapy. J Mol Cell Cardiol 47:445–455PubMedCrossRefGoogle Scholar
  16. 16.
    Boerries M, Most P, Gledhill JR, Walker JE, Katus HA, Koch WJ, Aebi U, Schoenenberger CA (2007) Ca2+ -dependent interaction of S100A1 with F1-ATPase leads to an increased ATP content in cardiomyocytes. Mol Cell Biol 27:4365–4373PubMedCrossRefGoogle Scholar
  17. 17.
    Most P, Bernotat J, Ehlermann P, Pleger ST, Reppel M, Börries M, Niroomand F, Pieske B, Janssen PM, Eschenhagen T, Karczewski P, Smith GL, Koch WJ, Katus HA, Remppis A (2001) S100A1: a regulator of myocardial contractility. Proc Natl Acad Sci USA 98:13889–13894PubMedCrossRefGoogle Scholar
  18. 18.
    Most P, Remppis A, Pleger ST, Löffler E, Ehlermann P, Bernotat J, Kleuss C, Heierhorst J, Ruiz P, Witt H, Karczewski P, Mao L, Rockman HA, Duncan SJ, Katus HA, Koch WJ (2003) Transgenic overexpression of the Ca2+ binding protein S100A1 in the heart leads to increased in vivo myocardial contractile performance. J Biol Chem 278:33809–33817PubMedCrossRefGoogle Scholar
  19. 19.
    Most P, Seifert H, Gao E, Funakoshi H, Völkers M, Heierhorst J, Remppis A, Pleger ST, DeGeorge BR Jr, Eckhart AD, Feldman AM, Koch WJ (2006) Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction. Circulation 114:1258–1268PubMedCrossRefGoogle Scholar
  20. 20.
    Tsoporis JN, Marks A, Zimmer DB, McMahon C, Parker TG (2003) The myocardial protein S100A1 plays a role in the maintenance of normal gene expression in the adult heart. Mol Cell Biochem 242:27–33PubMedCrossRefGoogle Scholar
  21. 21.
    Völkers M, Loughrey CM, Macquaide N, Remppis A, DeGeorge BR Jr, Wegner FV, Friedrich O, Fink RH, Koch WJ, Smith GL, Most P (2007) S100A1 decreases calcium spark frequency and alters their spatial characteristics in permeabilized adult ventricular cardiomyocytes. Cell Calcium 41:135–143PubMedCrossRefGoogle Scholar
  22. 22.
    Most P, Pleger ST, Völkers M, Heidt B, Boerries M, Weichenhan D, Löffler E, Janssen PM, Eckhart AD, Martini J, Williams ML, Katus HA, Remppis A, Koch WJ (2004) Cardiac adenoviral S100A1 gene transfer rescues failing myocardium. J Clin Invest 114:1550–1563PubMedGoogle Scholar
  23. 23.
    Pleger ST, Remppis A, Heidt B, Völkers M, Chuprun JK, Kuhn M, Zhou RH, Gao E, Szabo G, Weichenhan D, Müller OJ, Eckhart AD, Katus HA, Koch WJ, Most P (2005) S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction. Mol Ther 12:1120–1129PubMedCrossRefGoogle Scholar
  24. 24.
    Rohde D, Ritterhoff J, Voelkers M, Katus HA, Parker TG, Most P (2010) S100A1: a multifaceted therapeutic target in cardiovascular disease. J Cardiovasc Transl Res 3:525–537, ReviewPubMedCrossRefGoogle Scholar
  25. 25.
    Völkers M, Rohde D, Goodman C, Most P (2010) S100A1: a regulator of striated muscle sarcoplasmic reticulum Ca2+ handling, sarcomeric, and mitochondrial function. J Biomed Biotechnol 2010:178614PubMedCrossRefGoogle Scholar
  26. 26.
    Brinks H, Rohde D, Voelkers M, Qiu G, Pleger ST, Herzog N, Rabinowitz J, Ruhparwar A, Silvestry S, Lerchenmüller C, Mather PJ, Eckhart AD, Katus HA, Carrel T, Koch WJ, Most P (2011) S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes. J Am Coll Cardiol 58:966–973PubMedCrossRefGoogle Scholar
  27. 27.
    Maurice JP, Hata JA, Shah AS, White DC, McDonald PH, Dolber PC, Wilson KH, Lefkowitz RJ, Glower DD, Koch WJ (1999) Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery. J Clin Invest 104:21–29PubMedCrossRefGoogle Scholar
  28. 28.
    Hajjar RJ, Schmidt U, Matsui T, Guerrero JL, Lee KH, Gwathmey JK, Dec GW, Semigran MJ, Rosenzweig A (1998) Modulation of ventricular function through gene transfer in vivo. Proc Natl Acad Sci USA 95:5251–5256PubMedCrossRefGoogle Scholar
  29. 29.
    Hoshijima M, Ikeda Y, Iwanaga Y, Minamisawa S, Date MO, Gu Y, Iwatate M, Li M, Wang L, Wilson JM, Wang Y, Ross J Jr, Chien KR (2002) Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med 8:864–871PubMedGoogle Scholar
  30. 30.
    Boekstegers P, von Degenfeld G, Giehrl W, Heinrich D, Hullin R, Kupatt C, Steinbeck G, Baretton G, Middeler G, Katus HA, Franz WM (2000) Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins. Gene Ther 7:232–240PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Patrick Most
    • 1
    Email author
  • Philip Raake
    • 2
  • Christophe Weber
    • 1
  • Hugo A. Katus
    • 2
  • Sven T. Pleger
    • 1
  1. 1.Department of Internal Medicine III, Center for Molecular and Translational CardiologyUniversity of HeidelbergHeidelbergGermany
  2. 2.Department of Internal Medicine IIIUniversity of HeidelbergHeidelbergGermany

Personalised recommendations