Endothelin receptor antagonism attenuates cardiomyocyte apoptosis after induction of ischemia in rats.
OBJECTIVE
Apoptosis has recently been implicated as a process that may contribute to loss of cardiomyocytes and to adverse myocardial remodeling in congestive heart failure (CHF). We investigated to what extent myocardial ischemia and CHF lead to induction of apoptotic gene programs and loss of cardiomyocytes through apoptosis, and subsequently to what extent the beneficial effects of endothelin (ET) receptor antagonism after myocardial infarction (MI) could be attributed to reduction of apoptotic cell loss in the myocardium.


METHODS
Northern blot analysis, analysis of DNA fragmentation, and immunohistochemical analysis were performed after induction of MI in rats.


RESULTS
After induction of MI, the mRNA levels of the pro-apoptotic genes FAS, BAX, P53, and CASPASE-1 were significantly increased in the non-ischemic region of the left ventricle (LV) with highest levels of expression in the peri-infarct area. High levels of FAS, BAX, P53, and CASPASE-1 mRNA were also observed in the infarcted region. Concomitantly, numerous TUNEL-positive cells and internucleosomal degradation of DNA were found in tissue from the peri-infarct area and in the infarcted zone, indicating apoptotic cell death. Treatment with bosentan, a mixed ET(A)/ET(B) receptor antagonist, during the first 24 h after induction of MI significantly reduced the area of TUNEL-positive myocardium in the ischemic region (64 +/- 2% of LV circumference in the vehicle group vs 55 +/- 2% of LV circumference in the bosentan group, p < 0.05). Consistently, bosentan also caused a similar reduction of infarct size.


CONCLUSIONS
Our data demonstrate activation of pro-apoptotic genes and provide evidence of cardiomyocyte apoptosis in the viable peri-infarct area and in the infarcted region after MI in rats. Intervention with bosentan may attenuate cardiomyocyte cell loss through apoptosis in the area at risk after induction of ischemia.
Oie
Erik
E
Merck Sharp & Dohme Cardiovascular Research Center, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway.
Clausen
Ole Petter F
OP
Yndestad
Arne
A
Grøgaard
Haakon K
HK
Attramadal
Håvard
H
ØIje
Erik
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000077300:Bosentan; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan