Crosstalks among the intracellular signaling pathways in the failing myocardium

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The objective of this project was to elucidate the crosstalks among the intracellular signaling pathways in the development of the failing or hypertrophied myocardium. We performed the following studies to clarify these points :1) Functional significance and transcriptional regulation of inducible nitric oxide synthase in cardiac myocytes : Using cultured neonatal rat or chick embryonic cardiac myocytes, we analyzed transcriptional regulation of the iNOS gene and functional significance of the induced iNOS.In transcription of the rat iNOS gene, crosstalks among multiple kinases (A kinase, tyrosine kinases) as well as multiple nuclear factors (NF-kappaB,IRF-1, C/EBPbeta, CREB) playd important roles (Kinugawa K,et al, Circ Res, 1997). Furthermore, the induced iNOS exerted negative myocardial effects in the cultured cardiac myocytes (Kinugawa K,et al, Am J Physiol, 1997, Shimizu T,et al, Cardiovasc Res, in press).2) Molecular mechanisms underlying direct growth-promoting effects of platelet-derived growth factor (PDGF) on cardiac myocytes : PDGF promoted the growth of the chick embryonic ventricular myocytes probably through induction of the immediate-early gene, c-fos, activation of MAP kinases, and activation of the transcription factor AP1.3) Crosstalks among the intracellular signaling pathways in the negative myocardial effects of cytokines : Using adult guinea pig ventricular myocytes, we compared the effects of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha on myocardial function. Both IL-6 and TNF-alpha decreased the Ca^<2+> channel current augmented by isoproterenol treatment, while these cytokines did not affect the Ca^<2+> channel current at the basal states.4) Intracellular signaling pathways responsible for apoptosis of cardiac myocytes : In the myocardial apoptosis induced by interferon-gamma, the important roles of activation of the transcription factor IRF-1 and induction of caspase 3 were suggested.