15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and perillic-acid

Interleukin (IL)-33 is a member of the IL-1 family and is able to act cardioprotective. The aim of this study was to investigate the regulation of IL-33 by 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitors (statins) and bisphosphonates (BPs) in human cardiac tissue. The lipophilic fluvastatin, simvastatin, atorvastatin, and lovastatin as well as the nitrogenous BPs alendronate and ibandronate, but not hydrophilic pravastatin increased IL-33 mRNA and intracellular IL-33 protein levels in both human adult cardiac myocytes (HACM) and fibroblasts (HACF). Additionally, fluvastatin reduced soluble ST2 secretion from HACM. IL-33 was also up-regulated by the general inhibitor of prenylation perillic acid, a RhoA kinase inhibitor Y-27632, and by latrunculin B, but statin-induced IL-33 expression was inhibited by mevalonate, geranylgeranyl pyrophosphate (GGPP) and RhoA activator U-46619. The IL-33 promoter was 2.3-fold more accessible in statin-treated HACM compared to untreated cells (P = 0.037). In explanted hearts of statin-treated patients IL-33 protein was up-regulated as compared with the hearts of non-statin-treated patients (P = 0.048). As IL-33 was previously shown to exert cardioprotective effects, one could speculate that such up-regulation of IL-33 expression in human cardiac cells, which might happen mainly through protein geranylgeranylation, could be a novel mechanism contributing to known cardioprotective effects of statins and BPs.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amides; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cyclohexenes; Cytokines; Diphosphonates; Fibroblasts; Fluvastatin; Gene Expression Regulation; Heart; Heart Diseases; Humans; Interleukin-33; Lovastatin; Mevalonic Acid; Monoterpenes; Myocardium; Myocytes, Cardiac; Pravastatin; Pyridines; rhoA GTP-Binding Protein; Simvastatin; Thiazolidines

An increased level of cytokine interleukin-1 (IL-1) has been detected around the site of stroke. However, the effect of IL-1beta on the basilar artery has received little attention. We evaluated the effects of IL-1beta on the contractile response of rat isolated basilar artery by measuring isometric tension change. IL-1beta (10 ng/ml) and phenylephrine (0.1 nM) markedly enhanced U46619 (30 and 100 nM)-induced basilar artery contraction. The IL-1beta-mediated potentiation was partly suppressed by zinc protoporphyrin (3 microM) and was abolished by tetrodotoxin (TTX, 100 nM), (-)-perillic acid (1 microM), PD98059 (0.3 microM), SB203580 (1 microM) and prazosin (1 microM). Our data suggest that IL-1beta (10 ng/ml) causes an enhancement of U46619-mediated basilar artery contraction that probably involves TTX-sensitive neuronal release of an alpha1-adrenoceptor agonist and activation of p42/p44 and p38 mitogen-activated protein kinases/p21(ras) pathways.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic alpha-Antagonists; Animals; Basilar Artery; Calcium-Calmodulin-Dependent Protein Kinases; Cyclohexenes; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavonoids; Imidazoles; In Vitro Techniques; Interleukin-1; Male; Monoterpenes; Phenylephrine; Prazosin; Protoporphyrins; Pyridines; Rats; Rats, Sprague-Dawley; Tetrodotoxin; Vasoconstriction; Vasoconstrictor Agents