Mechanical Stretch Induced Interleukin‐18 (IL‐18) Expression through Angiotensin Subtype 1 Receptor (AT1R) and Endothelin‐1 in Cardiomyocytes

Abstract

Interleukin‐18 (IL‐18) is a proinflammatory cytokine with multiple biological functions. We and others have demonstrated that an increased level of circulating IL‐18 is one of the risk factors for cardiovascular diseases. Endothelin‐1 (ET‐1) has been reported to be a potent hypertrophy‐promoting factor through RhoA and Rho‐Kinase. Mechanical stretch induces a hypertrophic response, partly through the production of ET‐1 through Endothelin A receptor (ETAR). Moreover, it has also been reported that mechanical stretch induces cardiac hypertrophy through Angiotensin subtype 1 receptor (AT1R). However, the mechanism by which the IL‐18 gene expression is regulated in cardiomyocytes has not yet been fully understood. This study was designed to elucidate the functional significance of IL‐18 gene expression in response to mechanical stretch. Neonatal rat cardiomyocytes cultured on silicone dishes were subjected to stretch. The moderate 20% mechanical stretch resulted in the elevation of IL‐18 expression in a time‐dependent manner with the maximal level achieved 36 hours after the stretch. Olmesartan, AT1R antagonist inhibited stretch‐induced IL‐18 expression. ETAR blockade BQ123 inhibited stretch‐induced IL‐18 expression. However, the Endothelin B receptor (ETBR) receptor blockade BQ788 did not inhibit this reaction. ET‐1 induced IL‐18 expression, with a peak induction after 4 hours of incubation. These results might suggest that stretch stimulation of cardiomyocytes induced ET‐1 and, subsequently, ET‐1 up‐regulated the IL‐18 expression. Furthermore, Fasudil, a Rho‐Kinase inhibitor, and Simvastatin, a HMG‐CoA reductase inhibitor, led to a significant reduction in mechanical stretch‐induced IL‐18 expression. These results indicated, for the first time, that IL‐18 expression is induced by mechanical stretch in cardiomyocytes via the ETAR, AT1R, and the Rho/Rho‐K pathways. The induction of IL‐18 from cardiomyocytes by mechanical stress might cause the deterioration of cardiac functions in autocrine and paracrine fashion. The inhibition of IL‐18 expression induced by mechanical stress might be one of the mechanisms that account for the beneficial cardiovascular effects of AT1R antagonist, ETAR blockade, Statin, and Rho‐Kinase inhibitor.