P94PPAR agonists attenuated leptin induces endothelin-1-Rho/Rho-kinase-interleukin-18 pathway in cardiomyocytes

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Leptin is known to be an adipocyte-derived hormone and regulates weight control and energy metabolism. Recent studies indicate that leptin may contribute to heart failure. Interleukin-18 (IL-18), a member of the IL-1 family, is a proinflammatory cytokine with multiple biological functions. IL-18 induces myocardial hypertrophy, loss of contractility of cardiomyocytes and apoptosis leading myocardial dysfunction. Increased levels of circulating IL-18 are thought to be one of risk factors for heart failure. However, the effect and mechanism by which leptin induces heart failure with inflammatory cytokine were still unclear. Therefore, in the present study, we examined how leptin induces heart failure with increased IL-18.


We used cultured rat neonatal cardiomyocytes stimulated with leptin in order to measure IL-18 mRNA and protein expression, and Rho-kinase and NF-kB activity. We also investigated the effects of peroxisome proliferator-activated receptors (PPAR) agonists on these actions.


Leptin increased IL-18 mRNA and protein expression with dose- and time-dependent manner. BQ123, an endothelin A receptor (ETAR) antagonist inhibited leptin-induced IL-18 expression. Moreover, leptin induced endothelin-1(ET-1) production in cultured media and ET-1 increased IL-18 expression. These results indicate leptin induces IL-18 expression intermediates ET-1 via ETAR. Furthermore, C3 toxin, RhoA inhibitor, fasudil, Rho-kinase inhibitor, simvastatin, an HMG-CoA reductase inhibitor, and PPAR agonists, pioglitazone and bezafibrate led to a significant reduction in leptin-induced IL-18 expression. On the other hand, leptin up-regulated the activities of Rho-kinase and NF-kB. Western blots showed PPAR agonists attenuated the leptin-induced IL-18 expression and NF-kB activity but not the Rho-kinase activity. These results indicate that leptin induced the IL-18 expression through a mechanism that involves, at a minimum, ET-1 acting via the Rho/Rho-kinase and PPAR/NF-kB pathway and PPAR agonists attenuate the leptin-induced IL-18 expression at a point downstream from Rho/Rho-kinase.


The induction of IL-18 in cardiomyocytes by leptin and ET-1 might, therefore, cause a deterioration of the cardiac function in an autocrine and paracrine fashion. The inhibition of the IL-18 expression by PPAR agonists might be one of the mechanisms whereby the beneficial cardiovascular effects are exerted.

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