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    Blocking caspase-activated apoptosis improves contractility in failing myocardium (2001)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Laugwitz, K L
    Moretti, A
    Weig, H J
    Gillitzer, A
    Pinkernell, K
    Ott, T
    Pragst, I
    Städele, C
    Seyfarth, M
    Schömig, A
    Ungerer, M
    Quelle
    Human gene therapy; 12(17) — S. 2051–2063
    ISSN: 1043-0342
    Sprache
    Englisch
    Verweise
    Pubmed: 11747596
    Kontakt
    Klinik für kleine Haustiere

    Oertzenweg 19 b
    Haus 1
    14163 Berlin
    +49 30 838 62356
    kleintierklinik@vetmed.fu-berlin.de

    Abstract / Zusammenfassung

    Cardiac myocyte apoptosis has been demonstrated in end-stage failing human hearts. The therapeutic utility of blocking apoptosis in congestive heart failure (CHF) has not been elucidated. This study investigated the role of caspase activation in cardiac contractility and sarcomere organization in the development of CHF. In a rabbit model of heart failure obtained by rapid ventricular pacing, we demonstrate, using in vivo transcoronary adenovirus-mediated gene delivery of the potent caspase inhibitor p35, that caspase activation is associated with a reduction in contractile force of failing myocytes by destroying sarcomeric structure. In this animal model gene transfer of p35 prevented the rise in caspase 3 activity and DNA-histone formation. Genetically manipulated hearts expressing p35 had a significant improvement in left ventricular pressure rise (+dp/dt), decreased end-diastolic chamber pressure (LVEDP), and the development of heart failure was delayed. To better understand this benefit, we examined the effects of caspase 3 on cardiomyocyte dysfunction in vitro. Microinjection of activated caspase 3 into the cytoplasm of intact myocytes induced sarcomeric disorganization and reduced contractility of the cells. These results demonstrate a direct impact of caspases on cardiac function and may lead to novel therapeutic strategies via antiapoptotic regimens.