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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Expression of constitutively stable hybrid hypoxia-inducible factor-1 protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury

¹Genzyme Corporation, Framingham, Massachusetts; and ²Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan

Submitted 30 July 2004 ; accepted in final form 12 October 2004

Preconditioning in cultured cardiomyocytes elevates the expression of several protective genes including Glut-4 and heat shock protein (HSP)70. Hypoxia-inducible factor-1 (HIF-1) is known to mediate the transcriptional activation of hypoxia-responsive genes. In this study, we examined the effect of adenovirus-mediated expression of constitutively stable hybrid forms of HIF-1 on cardiomyocyte viability and gene expression. Cultured neonatal rat cardiomyocytes were subjected to simulated ischemia-reperfusion with or without preinfection with recombinant adenoviral vectors [Ad2/HIF-1/herpes simplex virus protein VP16 and Ad2/HIF-1/nuclear factor-B (NF-B)]. Cellular viability and mRNA levels of several cardioprotective genes were measured. We demonstrated that infection with Ad2/HIF-1/VP16 and Ad2/HIF-1/NF-B mimicked the upregulation of the mRNA levels of vascular endothelial growth factor (VEGF), Glut-1, Glut-4, HSP70, and inducible NO synthase (iNOS) and the protection of cultured neonatal rat cardiomyocytes by late-phase preconditioning against simulated ischemia-reperfusion. The same dose of a control viral vector expressing no transgene had no effect. Preconditioning also elevated HIF-1 protein levels. These results suggest that adenovirus-mediated expression of HIF-1/VP16 or HIF-1/NF-B, a constitutively stable hybrid transcriptional factor, protected cultured neonatal cardiomyocytes against simulated ischemia-reperfusion injury by inducing multiple protective genes.

ischemic preconditioning; myocardial protection

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