title: 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.
authors.affiliation: Division of Coronary Heart Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya-City, Hyogo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Doi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sakoda
authors.forename: Takafumi
authors.initials: T
authors.lastname: Akagami
authors.forename: Toshio
authors.initials: T
authors.lastname: Naka
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Mori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsujino
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuyama
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Ohyanagi
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001629:Bezafibrate / Q000494:pharmacology; D002478:Cells, Cultured; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000502:physiology*; D020382:Interleukin-18 / Q000096:biosynthesis*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000502:physiology*; D000077205:Pioglitazone; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000502:physiology*
chemical_list: D017931:DNA Primers; D019332:Endothelin-1; D020382:Interleukin-18; D016328:NF-kappa B; D009842:Oligopeptides; D010456:Peptides, Cyclic; D047492:Peroxisome Proliferator-Activated Receptors; D010880:Piperidines; D045162:Thiazolidinediones; D000804:Angiotensin II; C086539:BQ 788; D000450:Aldosterone; D054460:rho-Associated Kinases; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D000077205:Pioglitazone; D001629:Bezafibrate