Novel bisindolylmaleimide derivative inhibits mitochondrial permeability transition pore and protects the heart from reperfusion injury.
Despite major advances in treating patients with coronary heart disease, reperfusion injury is still considered to be a major problem, especially in surgical settings. Here, we demonstrate the protective effects of a novel bisindolylmaleimide derivative, MS1 (2-[1-(3-aminopropyl)indol-3-yl]-3-(indol-3-yl)-N-methylmaleimide), against reperfusion injury of the heart. After anesthesia and artificial ventilation, Wistar rats were subjected to 30 min of left coronary artery occlusion followed by 120 min of reperfusion with or without treating the rats with MS1 (2.25 mumol.L-1.kg-1) before left coronary artery occlusion. Compared with the untreated hearts, MS1 treatment significantly reduced myocardial infarct size (35.1% +/- 3% vs. 75.5% +/- 5%, p < 0.001), reduced prevalence of apoptotic cells (2.6% +/- 0.5% vs. 12.2% +/- 2.1%, p < 0.001), prevented mitochondrial swelling and cytochrome c release, inhibited downregulation of antiapoptotic protein Bcl-2 expression, and suppressed caspase-3 activation. In contrast, pretreatment with atractyloside, a mitochondrial permeability transition pore opener, abolished the protective effects of MS1. In conclusion, MS1 inhibits pathologic opening of permeability transition pores and protects the heart against reperfusion injury and pathologic apoptosis.
Department of Surgery II, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
Rajesh Gopalrao
RG
Katare
Zou
Z
Zhitian
Mikiko
M
Sodeoka
Shiro
S
Sasaguri
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008301:Maleimides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar
C527045:2-(1-(3-aminopropyl)indol-3-yl)-3-(indol-3-yl)-N-methylmaleimide; D002316:Cardiotonic Agents; D007211:Indoles; D008301:Maleimides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D045304:Cytochromes c; D053148:Caspase 3; C088060:bisindolylmaleimide