EFFECTS OF TRANSFORMING GROWTH FACTOR-BETA ON CARDIAC CELLS

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Transforming growth factor-beta has previously been implicated in embryonic development of the heart as well as in repair of myocardial damage following ischemia/reperfusion injury. Based on these findings, we have focused our attention on direct effects of TGF-beta on neonatal rat cardiac myocytes. When cultured on fibroblast matrix, the beating rate of the myocytes is suppressed by treatment with inflammatory mediators such as interleukin-1, tumor necrosis factor, interferon gamma, as well as endotoxin, whereas the beating rate is maintained by the simultaneous addition of TGF-beta. We have shown that the ability of TGF-beta to antagonize the suppressive effects of interleukin-1 on the beating rate is due, in part, to its ability to suppress the induction of nitric oxide by these myocytes. This is the first demonstration of a direct link between secretion of nitric oxide and the function of cultured neonatal cardiac myocytes. TGF-beta antagonizes the induction of nitric oxide synthase by not only interleukin-1, but also by the other inflammatory mediators. Levels of cellular cyclic CMP parallel those of nitric oxide, in agreement with the published effects of nitric oxide on activation of guanylate cyclase. Preliminary studies of the effects of TGF-beta and interleukin-1 on calcium release in these myocytes suggest that some of their effects on the beating rate may involve the action of cyclic GMP on Na+/Ca2+ exchange. Finally, we show that the suppressive effects of nitric oxide on the beating rate can be overcome by altering either the set of cytokines or the matrix on which the myocytes are cultured, demonstrating that nitric oxide is but one of several parameters regulating the beating rate of the myocytes.