Novel Therapy for Heart Failure of cardiomyopathic Hamster with Gene Transfection of Hepatocyte Growth Factor

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1) We integrated rat Hepatocyte growth factor CDNA (rHGF) into PCAGGS plasmid vector, which has β-actin promoter and affinity to muscle cells (PCAGGS-rHGF). Likewise, we made PCAGGS-human HGR We could confirm expression of rHGF alone, and used this forthe experiment.2) Ultrasound alone did not enhance transfection of rHGF. Sonoporation wrth microbubble made rat myocardial culture cells excrete HGF into medium.3) We tried direct injection of genes into the heart of cardiomyopathic hamster. Reporter gene LacZ was found to be transfected in the myocaraium. There was no excretion of HGF protein into peripheral blood.4) In vivo electroporation of LacZ and interleukin 5 into skeletal musde of hamster successfully transfected these genes. We employed this method, 6 pulses of 100V 50 ms, as a standard in vivo transfection method.5) We tried in vivo electroponation of rHGF into tibialis anterior musde of cardiomyopathic hamsterTO-2 using the dose of 200, 400 and 800 μg. Dose of 800 μg. resulted into maximum blood concentration of HGF. This dose with standard in vivo transfection method turned out to be a sustained elevation of HGF concentration over 5 ng/mL. Cardiac function estimated by echo-Doppler improved in HGF-treated hamsters compared with normal control and placebo given hamsters. Myocardial fibrosis was suppressed and capillary density was increased in HGF-treated hamsters compared with placebo-given hamsters. Increase in MMP-1 activity might be attributable to one of possible mechanisms of beneficial effects of HGF treatment for heart failure in cardiomyopathic hamsters (submitted).