Myocardial protective effect of human recombinant hepatocyte growth factor for prolonged heart graft preservation in rats.
BACKGROUND
In heart transplantation, myocardial apoptosis during hypothermic storage contributes to graft dysfunction. On the other hand, hepatocyte growth factor (HGF) has been reported to be an antiapoptotic factor in the heart. Therefore, we assessed whether the administration of recombinant human HGF (rh-HGF) prevents apoptosis in the prolonged preserved myocardium, resulting in an improvement in the cardiac function of the graft.


METHODS
Isolated rat hearts were subjected to 4 hr (group A), 6 hr (group B), and 8 hr (group C: without rh-HGF vs. group D: with 100 microg of rh-HGF) of hypothermic storage followed by 60 min of normothermic reperfusion (n=5 in each group).


RESULTS
Compared with non-HGF-treated hearts (group C), HGF-treated hearts (group D) showed a significantly higher recovery rate of left ventricular developed pressure (38+/-5% vs. 58+/-6%, P<0.01) and maximum dp/dt (53+/-7% vs. 74+/-4%, P<0.01) and a lower rate of TUNEL-positive cardiomyocytes (7.8+/-6.0% vs. 25.3+/-8.9%, P<0.05) after 60 min of reperfusion. Western blot analysis revealed that c-Met/HGF receptor expression was stronger in the HGF-treated myocardium than in the non-HGF-treated myocardium after 8 hr of storage and was associated with a weaker expression of caspase-3 and a stronger expression of Bcl-xL after 60 min of reperfusion.


CONCLUSIONS
The administration of rh-HGF before storage improved cardiac function after prolonged myocardial preservation by preventing apoptosis through the c-Met/HGF receptor. Thus, the addition of rh-HGF in the storage solution may be a promising strategy for prolonged heart graft preservation.
Ryugo
Masahiro
M
Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Sawa
Yoshiki
Y
Ono
Masamichi
M
Fukushima
Norihide
N
Aleshin
Alexey N
AN
Mizuno
Shinya
S
Nakamura
Toshikazu
T
Matsuda
Hikaru
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015925:Cryopreservation; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D009926:Organ Preservation; 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*; D020127:Recovery of Function; D013194:Staining and Labeling; D013997:Time Factors; D051020:bcl-X Protein
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; D019859:Proto-Oncogene Proteins c-met; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases