Mechanical stretch induced interleukin-18 (IL-18) expression through Angiotensin subtype 1 receptor (AT1R) and endothelin-1 in cardiomyocytes.
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.
Naka
Toshio
T
Department of Internal Medicine, Division of Coronary Heart Disease, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Sakoda
Tsuyoshi
T
Doi
Takashi
T
Akagami
Takafumi
T
Tsujino
Takeshi
T
Masuyama
Tohru
T
Ohyanagi
Mitsumasa
M
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004548:Elasticity; D019332:Endothelin-1 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013314:Stress, Mechanical
D019332:Endothelin-1; D020382:Interleukin-18; D044140:Receptor, Angiotensin, Type 1