Philipp J Hohensinner1, Max Lenz2, Patrick Haider2, Julia Mayer3, Manuela Richter3, Christoph Kaun2, Laura Goederle4, Mira Brekalo2, Manuel Salzmann2, Smriti Sharma2, Michael B Fischer5, Stefan Stojkovic2, Daniel Ramsmayer2, Christian Hengstenberg2, Bruno K Podesser6, Kurt Huber7, Christoph J Binder4, Johann Wojta8, Walter S Speidl2. 1. Department of Internal Medicine II/Cardiology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria; Center for Biomedical Research, Medical University of Vienna, Vienna, Austria. 2. Department of Internal Medicine II/Cardiology, Medical University of Vienna, Vienna, Austria. 3. Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria. 4. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. 5. Clinic for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria; Department for Health Science and Biomedicine, Danube University Krems, Krems, Austria. 6. Center for Biomedical Research, Medical University of Vienna, Vienna, Austria. 7. 3(rd) Medical Department, Wilhelminenhospital, Vienna, Austria; Sigmund Freud University, Medical Faculty, Vienna, Austria. 8. Department of Internal Medicine II/Cardiology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria; Core Facilities, Medical University of Vienna, Vienna, Austria. Electronic address: johann.wojta@meduniwien.ac.at.
Abstract
BACKGROUND: Inflammation is a key process during atherosclerotic lesion development and propagation. Recent evidence showed clearly that especially the inhibition of interleukin (IL)-1β reduced atherosclerotic adverse events in human patients. Fatty acid oxidation (FAO) was previously demonstrated to interact with the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathway which is required for mature IL-1β secretion. To understand possible anti-inflammatory properties of FAO inhibition, we tested the effect of pharmacological FAO inhibition using the inhibitor for long-chain 3-ketoacyl coenzyme A thiolase trimetazidine on atherosclerotic plaque development and inflammation. EXPERIMENTAL APPROACH: The effect of FAO inhibition was determined in LDL-R-/- male mice on a C57/BL6 background. In vitro effects of trimetazidine treatment were analyzed in human umbilical vein endothelial cells and human monocyte derived macrophages. KEY RESULTS: We were able to demonstrate that inhibition of FAO reduced atherosclerotic plaque growth. We did not find direct anti-inflammatory properties of trimetazidine in endothelial cells or macrophages in vitro. However, we found that the activation of the NLRP3 system and the secretion of IL-1β were significantly reduced in macrophages after FAO inhibition. These results were confirmed in atherosclerotic lesions of mice treated with trimetazidine as they showed a significant reduction of IL-1β and cleaved caspase-1 in the atherosclerotic lesion as well as of IL-1β and IL-18 in the circulation. CONCLUSION: Overall, we therefore suggest that the main mechanism of reducing inflammation of trimetazidine and FAO inhibition is the reduction of the NLRP-3 activation leading to reduced levels of the proinflammatory cytokine IL-1β.
BACKGROUND:Inflammation is a key process during atherosclerotic lesion development and propagation. Recent evidence showed clearly that especially the inhibition of interleukin (IL)-1β reduced atherosclerotic adverse events in humanpatients. Fatty acid oxidation (FAO) was previously demonstrated to interact with the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathway which is required for mature IL-1β secretion. To understand possible anti-inflammatory properties of FAO inhibition, we tested the effect of pharmacological FAO inhibition using the inhibitor for long-chain 3-ketoacyl coenzyme A thiolase trimetazidine on atherosclerotic plaque development and inflammation. EXPERIMENTAL APPROACH: The effect of FAO inhibition was determined in LDL-R-/- male mice on a C57/BL6 background. In vitro effects of trimetazidine treatment were analyzed in human umbilical vein endothelial cells and human monocyte derived macrophages. KEY RESULTS: We were able to demonstrate that inhibition of FAO reduced atherosclerotic plaque growth. We did not find direct anti-inflammatory properties of trimetazidine in endothelial cells or macrophages in vitro. However, we found that the activation of the NLRP3 system and the secretion of IL-1β were significantly reduced in macrophages after FAO inhibition. These results were confirmed in atherosclerotic lesions of mice treated with trimetazidine as they showed a significant reduction of IL-1β and cleaved caspase-1 in the atherosclerotic lesion as well as of IL-1β and IL-18 in the circulation. CONCLUSION: Overall, we therefore suggest that the main mechanism of reducing inflammation of trimetazidine and FAO inhibition is the reduction of the NLRP-3 activation leading to reduced levels of the proinflammatory cytokine IL-1β.
Authors: Max Lenz; Manuel Salzmann; Cosmin I Ciotu; Christoph Kaun; Konstantin A Krychtiuk; Andreja Rehberger Likozar; Miran Sebestjen; Laura Goederle; Sabine Rauscher; Zoriza Krivaja; Christoph J Binder; Kurt Huber; Christian Hengstenberg; Bruno K Podesser; Michael J M Fischer; Johann Wojta; Philipp J Hohensinner; Walter S Speidl Journal: Proc Natl Acad Sci U S A Date: 2022-07-13 Impact factor: 12.779
Authors: Patrick Haider; Julia B Kral-Pointner; Manuel Salzmann; Florian Moik; Sonja Bleichert; Waltraud C Schrottmaier; Christoph Kaun; Mira Brekalo; Michael B Fischer; Walter S Speidl; Christian Hengstenberg; Bruno K Podesser; Kurt Huber; Ingrid Pabinger; Sylvia Knapp; Frank Brombacher; Christine Brostjan; Cihan Ay; Johann Wojta; Philipp J Hohensinner Journal: FASEB J Date: 2022-10 Impact factor: 5.834