Aldosterone induces interleukin-18 through endothelin-1, angiotensin II, Rho/Rho-kinase, and PPARs in cardiomyocytes

Abstract

Aldosterone (Aldo) is recognized as an important risk factor for cardiovascular diseases. IL-18 induces myocardial hypertrophy, loss of contractility of cardiomyocytes, and apoptosis leading myocardial dysfunction. However, so far, there have been few reports concerning the interaction between Aldo and IL-18. The present study examined the effects and mechanisms of Aldo on IL-18 expression and the roles of peroxisome proliferator-activated receptor (PPAR) agonists in rat cardiomyocytes. We used cultured rat neonatal cardiomyocytes stimulated with Aldo to measure IL-18 mRNA and protein expression, Rho-kinase, and NF-kappaB activity. We also investigated the effects of PPAR agonists on these actions. Aldo, endothelin-1 (ET-1), and angiotensin II (ANG II) increased IL-18 mRNA and protein expression. Mineralocorticoid receptor antagonists, endothelin A receptor antagonist, and ANG II receptor antagonist inhibited Aldo-induced IL-18 expression. Aldo induced ET-1 and ANG II production in cultured media. Moreover, Rho/Rho-kinase inhibitor and statin inhibited Aldo-induced IL-18 expression. On the other hand, Aldo upregulated the activities of Rho-kinase and NF-kappaB. PPAR agonists attenuated the Aldo-induced IL-18 expression and NF-kappaB activity but not the Rho-kinase activity. Our findings indicate that Aldo induces IL-18 expression through a mechanism that involves, at a minimum, ET-1 and ANG II acting via the Rho/Rho-kinase and PPAR/NF-kappaB pathway. The induction of IL-18 in cardiomyocytes by Aldo, ET-1, and ANG II 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.