Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF.
Using a rat model of ischemia/reperfusion injury, we demonstrate here that HGF is cardioprotective due to its antiapoptotic effect on cardiomyocytes. Following transient myocardial ischemia and reperfusion, c-Met/HGF receptor expression rapidly increased in the ischemic myocardium, an event accompanied by a dramatic increase in plasma HGF levels in the infarcted rats. When endogenous HGF was neutralized with a specific antibody, the number of myocyte cell deaths increased markedly, the infarct area expanded, and the mortality increased to 50%, as compared with a control group in which there was no mortality. Plasma from the myocardial infarcted rats had cardioprotective effects on primary cultured cardiomyocytes, but these effects were significantly diminished by neutralizing HGF. In contrast, recombinant HGF administration reduced the size of infarct area and improved cardiac function by suppressing apoptosis in cardiomyocytes. HGF rapidly augmented Bcl-xL expression in injured cardiomyocytes both in vitro and in vivo. As apoptosis of cardiomyocytes is one of the major contributors to the pathogenesis in subjects with ischemia/reperfusion injury, prevention of apoptosis may prove to be a reasonable therapeutic strategy. Supplements of HGF, an endogenous cardioprotective factor, may be found clinically suitable in treating subjects with myocardial infarction.
Nakamura
T
T
Division of Biochemistry, Department of Oncology, Biomedical Research Center B7, Osaka University Graduate School of Medicine, Suita, Japan. nakamura@onbich.med.osaka-u.ac.jp
Mizuno
S
S
Matsumoto
K
K
Sawa
Y
Y
Matsuda
H
H
Nakamura
T
T
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D006651:Histocytochemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017202:Myocardial Ischemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D051020:bcl-X Protein
D000906:Antibodies; C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein; D017228:Hepatocyte Growth Factor; D006861:Hydrogen Peroxide; D019859:Proto-Oncogene Proteins c-met; D020928:Mitogen-Activated Protein Kinases