Research for the reguration of the gene expression of glucose transporters in ischemic heart diseases and its application to gene therapy

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GLUT1 and GLUT4 are the primary isoforms of glucose transporters expressed in the myocardium. Expression of the GLUT1 gene has been shown to be increased in hypoxic cardiac myocytes. In the present study, we demonstrated hypoxia-mediated induction of GLUT4 gene expression in cultured neonatal rat cardiac myocytes exposed to persistent hypoxia. We also showed that the induction of GLUT1 and GLUT4 mRNAs upon hypoxia was much more abundant in cardiac myocytes than in non-myocytes. The induction of both mRNAs in hypoxic cardiac myocytes was completely abrogated by BAPTA-AM, suggesting the need for an elevated intracellular calcium ion concentration ([Ca^<2+>]_i) in this response. Furthermore, the induction of both mRNAs was attenuated by H7, suggesting the involvement of the protein kinase C (PKC) pathway as well. Nonetheless, our findings in this study suggest that GLUT1 and GLUT4 gene expressions are induced in distinctly different ways. To begin with, the time courses required for the induction of the two genes were different. Secondly, increases in [Ca^<2+>]_i at normoxia with A23187 or veratridine resulted in increases in GLUT1 mRNA but not in GLUT4 mRNA, suggesting that [Ca^<2+>]_i elevation alone is insufficient for the induction of GLUT4 mRNA.Thirdly, H7 only partially inhibited the induction of GLUT1 mRNA, but fully inhibited the induction of GLUT4 mRNA. These results suggest that [Ca^<2+>]_i elevation and PKC activation are both involved in the hypoxic induction of GLUT1 and GLUT4 gene expression, but that the regulatory mechanisms of these genes may differ in this process.