Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function.
Up-regulation of proapoptotic genes has been reported in heart failure and myocardial infarction. To determine whether caspase genes can affect cardiac function, a transgenic mouse was generated. Cardiac tissue-specific overexpression of the proapoptotic gene Caspase3 was induced by using the rat promoter of alpha-myosin heavy chain, a model that may represent a unique tool for investigating new molecules and antiapoptotic therapeutic strategies. Cardiac-specific Caspase3 expression induced transient depression of cardiac function and abnormal nuclear and myofibrillar ultrastructural damage. When subjected to myocardial ischemia-reperfusion injury, Caspase3 transgenic mice showed increased infarct size and a pronounced susceptibility to die. In this report, we document an unexpected property of the proapoptotic gene caspase3 on cardiac contractility. Despite inducing ultrastructural damage, Caspase3 does not trigger a full apoptotic response in the cardiomyocyte. We also implicate Caspase3 in determining myocardial infarct size after ischemia-reperfusion injury, because its cardiomyocyte-specific overexpression increases infarct size.
Condorelli
G
G
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107-5541, USA. gianluigi.condorelli@mail.tju.edu
Roncarati
R
R
Ross
J
J
Pisani
A
A
Stassi
G
G
Todaro
M
M
Trocha
S
S
Drusco
A
A
Gu
Y
Y
Russo
M A
MA
Frati
G
G
Jones
S P
SP
Lefer
D J
DJ
Napoli
C
C
Croce
C M
CM
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000502:physiology*; D053938:DNA Fragmentation; D018076:DNA, Complementary / Q000235:genetics; D004452:Echocardiography; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D017202:Myocardial Ischemia / Q000201:enzymology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000209:etiology
D018076:DNA, Complementary; D011993:Recombinant Fusion Proteins; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases