Zsofia Onodi1, Mihaly Ruppert2, Przemyslaw Leszek3, Viktoria Eva Toth1, Gabor Koncsos1, Tamas Radovits2, Peter Ferdinandy1, Zoltan V Varga1
1Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest
2Heart and Vascular Center, Semmelweis University, Budapest
3Department of Heart Failure and Transplantology, Cardinal Stefan Wyszyński Institute of Cardiology, Warszawa
Background: Inflammation and cytokine release is considered an important feature of progressive heart failure. Canakinumab, a monoclonal antibody against interleukin-1b (IL-1β), has been shown to provide benefit against cardiovascular events, suggesting that blockade of IL-1β secretion and signaling might be a promising new therapeutic target. Inflammasome activation is the main contributor to IL-1β maturation; nevertheless, the role of inflammasome activation in chronic heart failure is unknown. Therefore, we aimed to assess inflammasome activation in myocardial samples from end-stage failing human hearts.
Methods: Inflammasome activation was measured by immunobloting in left ventricular tissue samples harvested from end-stage failing human hearts. Monocytes and macrophages in human left ventricles were detected by immunohistochemistry. To investigate the molecular background of inflammasome activation, a series of cell culture experiments were performed on AC16 human cardiomyocytes and THP-1 human monocytic cell lines.
Results: Expression of AIM2 and NLRC4 increased in end-stage human failings hearts regardless of the etiology of heart failure. There was a robust infiltration of Iba1+ monocytes/macrophages in all groups of failing hearts. In vitro AIM2 inflammasome activation, as induced by transfection with double-stranded DNA [poly(deoxyadenylic-deoxythymidylic)] was reduced significantly by the pharmacological blockade of pannexin-1 channels.
Conclusions: AIM2 and NLRC4 inflammasome activation might contribute to chronic inflammation in heart failure. Our findings suggest that pannexin-1 channels might be a promising novel target to reduce inflammasome activation. We also hypothesize that cell death during the remodeling process associates with the release of damage-associated molecules (dsDNA, mtDNA, HMGB1), that in turn activate AIM2 inflammasome, ultimately leading to the chronic inflammatory reaction.
Doctoral School of Pharmaceutical Sciences
Experimental and Clinical Pharmacology
Supervisor: Zoltan Varga (e-mail: email@example.com)