Delayed activation of caspase-independent apoptosis during heart failure in transgenic mice overexpressing caspase inhibitor CrmA.
Although caspase activation is generally thought to be necessary to induce apoptosis, recent evidence suggests that apoptosis can be activated in the setting of caspase inhibition. In this study, we tested the hypothesis that caspase-independent apoptotic pathways contribute to the development of heart failure in the absence of caspase activation. Acute cardiomyopathy was induced using a single dose of doxorubicin (Dox, 20 mg/kg) injected into male wild-type (WT) and transgenic (Tg) mice with a cardiac-specific expression of cytokine response modifier A (CrmA), a known caspase inhibitor. Early (6 day) survival was significantly better in CrmA Tg (81%) than WT (38%) mice. Twelve days after Dox injection, however, the mortality benefit had dissipated, and increased cardiac apoptosis was observed in both groups. There was, however, a significantly greater release of apoptosis-inducing factor (AIF) from mitochondria to cytosol in CrmA Tg compared with WT mice, which suggests that an enhancement of activation in caspase-independent apoptotic pathways had occurred. The administration of a poly(ADP-ribose) polymerase-1 inhibitor, 4-amino-1,8-naphthalimide (4-AN), to Dox-treated mice resulted in significantly improved cardiac function, a significant blockade of AIF released from mitochondria, and decreased cardiac apoptosis. There were also significantly improved survival in WT (18% without 4-AN vs. 89% with 4-AN) and CrmA Tg (13% without 4-AN vs. 93% with 4-AN) mice 12 days after Dox injection. In conclusion, these findings suggest that apoptosis can be induced in the heart lacking caspase activation via caspase-independent pathways and that enabling the inhibition of AIF activation may provide a significant cardiac benefit.
Bae
Soochan
S
Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Siu
Parco M
PM
Choudhury
Sangita
S
Ke
Qingen
Q
Choi
Jun H
JH
Koh
Young Y
YY
Kang
Peter M
PM
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism; D053644:Naphthalimides / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones / Q000494:pharmacology; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D051033:Apoptosis Inducing Factor; D061945:Caspase Inhibitors; D053644:Naphthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones; D015843:Serpins; D014764:Viral Proteins; C086538:4-amino-1,8-naphthalimide; D004317:Doxorubicin; C074641:interleukin-1beta-converting enzyme inhibitor; D015057:1-Naphthylamine; D020169:Caspases