title: Blocking caspase-activated apoptosis improves contractility in failing myocardium.
abstract: 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.
authors.affiliation: Medizinische Klinik and Deutsches Herzzentrum München, 81675 Munich, Germany. laugwitz@med1.med.tu-muenchen.de
authors.forename: K L
authors.initials: KL
authors.lastname: Laugwitz
authors.forename: A
authors.initials: A
authors.lastname: Moretti
authors.forename: H J
authors.initials: HJ
authors.lastname: Weig
authors.forename: A
authors.initials: A
authors.lastname: Gillitzer
authors.forename: K
authors.initials: K
authors.lastname: Pinkernell
authors.forename: T
authors.initials: T
authors.lastname: Ott
authors.forename: I
authors.initials: I
authors.lastname: Pragst
authors.forename: C
authors.initials: C
authors.lastname: Städele
authors.forename: M
authors.initials: M
authors.lastname: Seyfarth
authors.forename: A
authors.initials: A
authors.lastname: Schömig
authors.forename: M
authors.initials: M
authors.lastname: Ungerer
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D053938:DNA Fragmentation; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D006352:Heart Ventricles / Q000201:enzymology / Q000503:physiopathology; D008164:Luminescent Proteins; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D009929:Organ Size; D010138:Pacemaker, Artificial; D011817:Rabbits; D051381:Rats; D012518:Sarcomeres / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013610:Tachycardia / Q000503:physiopathology; D013997:Time Factors; D019076:Transgenes / Q000235:genetics
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases