A novel SOD-mimetic permeability transition inhibitor agent protects ischemic heart by inhibiting both apoptotic and necrotic cell death.
In ischemia-reperfusion injuries, elevated calcium and reactive oxygen species (ROS) induce mitochondrial permeability transition (mPT), which plays a pivotal role in mediating damages and cell death. Inhibition of mPT decreases necrotic cell death; however, during reperfusion, the continuous production of ROS may contribute to the temporary opening of the pore and thus the onset of the delayed apoptotic cell death. Based on amiodarone structure, we developed the first SOD-mimetic mPT inhibitor (HO-3538) that can eliminate ROS in the microenvironment of the permeability pore. In isolated mitochondria, HO-3538 inhibited mPT and the release of proapoptotic mitochondrial proteins. It had a ROS scavenging effect and antiapoptotic effect in a cardiomyocyte line and it diminished release of mitochondrial proapoptotic proteins. Furthermore, HO-3538 significantly enhanced the recovery of mitochondrial energy metabolism and functional cardiac parameters; decreased infarct size, lipid peroxidation, and protein oxidation; and suppressed necrotic as well as apoptotic cell death pathways in Langendorff-perfused hearts. In these respects it was somewhat superior to its two constituents, amiodarone and a pyrrol-derivative free radical scavenger. These data suggest that the SOD-mimetic mPT inhibitors are ideal candidates for drug development for the alleviation of postinfarct myocardial injuries.
Bognar
Zita
Z
Department of Biochemistry and Medical Chemistry, Faculty of Medicine, University of Pecs, H-7624 Pecs, Hungary.
Kalai
Tamas
T
Palfi
Anita
A
Hanto
Katalin
K
Bognar
Balazs
B
Mark
Laszlo
L
Szabo
Zoltan
Z
Tapodi
Antal
A
Radnai
Balazs
B
Sarszegi
Zsolt
Z
Szanto
Arpad
A
Gallyas
Ferenc
F
Hideg
Kalman
K
Sumegi
Balazs
B
Varbiro
Gabor
G
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000473:pathology*; D019169:Jurkat Cells; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology; D009336:Necrosis / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D013482:Superoxide Dismutase / Q000378:metabolism*
C517000:HO-3538; D045304:Cytochromes c; D013482:Superoxide Dismutase; D000638:Amiodarone