Direct and indirect effects of aldosterone on cyclooxygenase-2 and interleukin-6 expression in rat cardiac cells in culture and after myocardial infarction

Abstract

Aldosterone contributes to cardiac failure, which is associated with induction of inflammatory mediators. Moreover, aldosterone was shown to induce a vascular inflammatory phenotype in the rat heart. Using Western blotting and/or real-time RT-PCR, we examined the effect of aldosterone on the expression of the proinflammatory molecules, cyclooxygenase-2 (COX-2), and IL-6 in neonatal rat ventricular cardiac myocytes and fibroblasts as well as in adult cardiomyocytes after myocardial infarction. In cardiomyocytes, aldosterone induced COX-2 but not IL-6 expression. After 4-18 h of stimulation with 1 μM aldosterone, a significant increase in COX-2 protein expression was observed, preceded by an increase of COX-2 mRNA levels. After 18 h treatment, 100 nM and 1 μM aldosterone increased COX-2 protein amount by 2- and 4-fold, respectively. Consistently, aldosterone increased by 2.5-fold prostaglandin E2 secretion in cardiomyocytes. In cardiac fibroblasts, aldosterone increased neither COX-2 nor IL-6 mRNA expression. Interestingly, prostaglandin E2 (100 nM) strongly induced both proinflammatory molecules in fibroblasts and cardiomyocytes. Our results indicate that aldosterone directly induces COX-2 expression in cardiomyocytes and suggest that the subsequent increase in prostaglandin secretion may act in an autocrine and/or paracrine manner inducing in turn COX-2 and IL-6 expression. In vivo, myocardial infarction strongly increased both COX-2 and IL-6 expression in ventricular cardiomyocytes. Administration of the aldosterone antagonist RU28318 completely prevented COX-2 induction by infarction and partially inhibited the increase in IL-6 mRNA. These data suggest that after myocardial infarction, mineralocorticoid receptor activity is responsible for COX-2 induction and indirectly participates in IL-6 expression in cardiomyocytes.