title: Effects of ACE inhibition on myocardial apoptosis in an ischemia-reperfusion rat heart model.
abstract: Myocardial ischemia-reperfusion injury involves necrosis and apoptosis. The inhibition of angiotensin-converting enzyme (ACE) has been reported to suppress infarct size. In this study, it was investigated whether an ACE inhibitor affected myocardial apoptosis and apoptosis-related proteins in rats with experimental myocardial infarction. Anesthetized Sprague-Dawley rats were divided into four groups. Group I underwent 30 minutes of left coronary artery occlusion followed by 24 hours of reperfusion (control group); Group II underwent oral administration of the ACE inhibitor quinapril (10 mg/kg/day) before coronary occlusion (quinapril group); Group III underwent administration of the bradykinin B(2)-receptor antagonist Hoe 140 (250 microg/kg/day, subcutaneously) with quinapril (quinapril + Hoe 140 group); and Group IV underwent administration of Hoe 140 alone (Hoe 140 group). After reperfusion, myocardial infarct size was determined by triphenyltetrazolium chloride staining. Myocardial apoptosis was detected immunohistologically using terminal deoxynucleotidyl transferase-mediated nick end labeling staining and DNA electrophoresis. Myocardial caspase-3 activation was analyzed by Western blot and the expressions of Bcl-xL and Bax proteins were detected immunohistochemically. Quinapril significantly reduced the ratio of myocardial infarct size in the ischemic area at risk. In addition, quinapril significantly suppressed the incidence of apoptotic myocytes around the necrotic region (from 18.9 +/- 0.8% to 8.6 +/- 1.0%; P < 0.0001), the intensity of DNA ladder formation, and the activation of caspase-3. Hoe 140 attenuated these protective effects of quinapril. In the immunohistochemical study, Bax and Bcl-xL were expressed in myocytes, and ischemia-reperfusion abolished both proteins in the center region of ischemia. The Bax staining was equally observed among all groups. However, Bcl-xL staining remained in the ischemic area widely after quinapril treatment. In addition, Hoe 140 also depleted this effect of quinapril. These results suggest that inhibition of ACE reduces myocardial infarction and apoptosis via the bradykinin B(2) receptor in part. The antiapoptotic effect of the ACE inhibitor is attributed to the changing expression of Bcl-xL.
authors.affiliation: Second Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kobara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kambayashi
authors.forename: Akiko
authors.initials: A
authors.lastname: Mano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamanaka
authors.forename: Jun
authors.initials: J
authors.lastname: Shiraishi
authors.forename: Natsuya
authors.initials: N
authors.lastname: Keira
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.forename: Jun
authors.initials: J
authors.lastname: Asayama
authors.forename: Shinji
authors.initials: S
authors.lastname: Fushiki
authors.forename: Masao
authors.initials: M
authors.lastname: Nakagawa
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases