Role of AIF in cardiac apoptosis in hypertrophic cardiomyocytes from Dahl salt-sensitive rats.
OBJECTIVE
The caspases are thought to be central mediators of the apoptotic program, but recent data indicate that apoptosis may also be mediated by caspase-independent mechanisms such as apoptosis-inducing factor (AIF). The role of AIF-induced apoptosis in heart, however, is currently not well understood. The aim of this study was to investigate the presence of and conditions for AIF-induced cardiac apoptosis in vitro.


RESULTS
Hypertrophic cardiomyocyte (H-CM) cultures were prepared from the hearts of Dahl salt-sensitive rats fed a high salt diet. Apoptotic stimulation induced by hypoxia/reoxygenation or staurosporine (1 microM) enhanced AIF release in H-CMs compared with non-hypertrophic cardiomyocytes (N-CMs). Caspase inhibition using zVAD.fmk (25 microM) or overexpression of CrmA using recombinant adenovirus only partially protected N-CMs from apoptosis (63 +/- 0.93%) and provided no significant protection against apoptosis in hypertrophic cells (23 +/- 1.03%). On the other hand, poly-ADP-ribose polymerase inhibition using 4-AN (20 microM) during apoptotic stimulation blocked the release of AIF from mitochondria and significantly improved cell viability in hypertrophied cardiomyocytes (74 +/- 1.18%).


CONCLUSIONS
A caspase-dependent, apoptotic pathway is important for N-CM death, whereas a caspase-independent, AIF-mediated pathway plays a critical role in H-CMs.
Choudhury
Sangita
S
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Bae
Soochan
S
Kumar
Sheetal R
SR
Ke
Qingen
Q
Yalamarti
Bhargavi
B
Choi
Jun H
JH
Kirshenbaum
Lorrie A
LA
Kang
Peter M
PM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000502:physiology*; D006332:Cardiomegaly / Q000473:pathology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D005260:Female; D032383:Myocytes, Cardiac / Q000473:pathology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D020303:Rats, Inbred Dahl
C494831:Aifm1 protein, rat; D000590:Amino Acid Chloromethyl Ketones; D051033:Apoptosis Inducing Factor; D061945:Caspase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D020169:Caspases