Higenamine reduces apoptotic cell death by induction of heme oxygenase-1 in rat myocardial ischemia-reperfusion injury.
Pharmacological modulation of heme oxygenase (HO) gene expression may have significant therapeutic potential in oxidant-induced disorders, such as ischemia reperfusion (I/R) injury. Higenamine is known to reduce ischemic damages by unknown mechanism(s). The protective effect of higenamine on myocardial I/R-induced injury was investigated. Ligation of rat left anterior descending coronary artery for 30 min under anesthesia was done and followed by 24 h reperfusion before sacrifice. I/R-induced myocardial damages were associated with mitochondria-dependent apoptosis as evidenced by the increase of cytochrome c release and caspase-3 activity. Administration of higenamine (bolus, i.p) 1 h prior to I/R-injury significantly decreased the release of cytochrome c, caspase-3 activity, and Bax expression but up-regulated the expression of Bcl-2, HO-1, and HO enzyme activity in the left ventricles, which were inhibited by ZnPP IX, an enzyme inhibitor of HO-1. In addition, DNA-strand break-, immunohistochemical-analysis, and TUNEL staining also supported the anti-apoptotic effect of higenamine in I/R-injury. Most importantly, administration of ZnPP IX inhibited the beneficial effect of higenamine. Taken together, it is concluded that HO-1 plays a core role for the protective action of higenamine in I/R-induced myocardial injury.
Lee
Young Soo
YS
Department of Pharmacology, College of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Korea.
Kang
Young Jin
YJ
Kim
Hye Jung
HJ
Park
Min Kyu
MK
Seo
Han Geuk
HG
Lee
Jae Heun
JH
Yun-Choi
Hye Sook
HS
Chang
Ki Churl
KC
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D045362:Cytochromes c2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000503:physiopathology* / Q000517:prevention & control; D010084:Oxidation-Reduction / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000470:Alkaloids; D000975:Antioxidants; C494828:Bax protein, rat; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011524:Protoporphyrins; D044005:Tetrahydroisoquinolines; D051028:bcl-2-Associated X Protein; D030421:Peroxynitrous Acid; C017803:zinc protoporphyrin; D045304:Cytochromes c; D045362:Cytochromes c2; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; C012348:higenamine