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Cardioprotective cytokine interleukin-33 is up-regulated by statins in human cardiac tissue

Richard Pentz1, Christoph Kaun1, Barbara Thaler1

  • 1Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.

Journal of Cellular and Molecular Medicine
|September 15, 2018
PubMed

Insights

Lipophilic statins and nitrogenous bisphosphonates increase cardioprotective Interleukin-33 (IL-33) in human heart cells. This upregulation, potentially via protein geranylgeranylation, may explain their protective effects.

Area of Science:

  • Cardiovascular Biology
  • Molecular Pharmacology
  • Immunology

Background:

  • Interleukin-33 (IL-33), a member of the IL-1 family, exhibits cardioprotective properties.
  • Statins (HMG-CoA reductase inhibitors) and bisphosphonates (BPs) are widely used medications with known cardiovascular benefits.
  • The precise molecular mechanisms underlying the cardioprotective effects of statins and BPs are not fully elucidated.

Purpose of the Study:

  • To investigate the regulation of IL-33 expression by statins and bisphosphonates in human cardiac cells.
  • To explore the potential molecular pathways involved in statin- and BP-induced IL-33 modulation.
  • To correlate in vitro findings with IL-33 levels in human cardiac tissue from patients treated with statins.

Main Methods:

  • Treatment of human adult cardiac myocytes (HACM) and fibroblasts (HACF) with various lipophilic and hydrophilic statins, and nitrogenous bisphosphonates.
  • Measurement of IL-33 mRNA and intracellular protein levels, and soluble ST2 secretion.
  • Investigation of signaling pathways using prenylation inhibitors, RhoA kinase inhibitors, and activators; assessment of IL-33 promoter accessibility.
  • Analysis of IL-33 protein levels in explanted human hearts from statin-treated and non-treated patients.

Main Results:

  • Lipophilic statins (fluvastatin, simvastatin, atorvastatin, lovastatin) and nitrogenous BPs (alendronate, ibandronate) significantly increased IL-33 mRNA and protein in HACM and HACF.
  • Hydrophilic pravastatin did not affect IL-33 levels; fluvastatin reduced soluble ST2 secretion.
  • Statin-induced IL-33 expression was modulated by prenylation and RhoA signaling pathways, with increased IL-33 promoter accessibility observed.
  • Explanted hearts from statin-treated patients showed significantly higher IL-33 protein levels compared to controls.

Conclusions:

  • Lipophilic statins and nitrogenous bisphosphonates upregulate IL-33 expression in human cardiac cells, potentially through mechanisms involving protein geranylgeranylation.
  • This IL-33 upregulation may represent a novel mechanism contributing to the established cardioprotective effects of these drug classes.
  • Findings suggest a potential therapeutic link between statins, bisphosphonates, IL-33, and cardiovascular protection.

Keywords:
bisphosphonatescardiac cellsinterleukin-33pleiotropicstatins

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