Cardioprotective cytokine interleukin33 is upregulated by statins in human cardiac tissue

Abstract

Interleukin (IL)33 is a member of the IL1 family and is able to act cardioprotective. The aim of this study was to investigate the regulation of IL33 by 3hydroxy3methylglutarylcoenzymeA (HMGCoA) 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 IL33 mRNA and intracellular IL33 protein levels in both human adult cardiac myocytes (HACM) and fibroblasts (HACF). Additionally, fluvastatin reduced soluble ST2 secretion from HACM. IL33 was also upregulated by the general inhibitor of prenylation perillic acid, a RhoA kinase inhibitor Y27632, and by latrunculin B, but statininduced IL33 expression was inhibited by mevalonate, geranylgeranyl pyrophosphate (GGPP) and RhoA activator U46619. The IL33 promoter was 2.3fold more accessible in statintreated HACM compared to untreated cells (P = 0.037). In explanted hearts of statintreated patients IL33 protein was upregulated as compared with the hearts of nonstatintreated patients (P = 0.048). As IL33 was previously shown to exert cardioprotective effects, one could speculate that such upregulation of IL33 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.(VLID)481831