Annelot C M van Esbroeck1, Zoltan V Varga2, Xinyu Di3, Eva J van Rooden1, Viktória E Tóth4, Zsófia Onódi4, Mariusz Kuśmierczyk5, Przemyslaw Leszek5, Péter Ferdinandy6, Thomas Hankemeier3, Mario van der Stelt1, Pál Pacher7. 1. Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, the Netherlands. 2. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, USA; Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary. 3. Department of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands. 4. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary. 5. Department of Heart Failure and Transplantology, Cardinal Stefan Wyszyński Institute of Cardiology, Warszawa, Poland. 6. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary. 7. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, USA. Electronic address: pacher@mail.nih.gov.
Abstract
AIM: Acute myocardial infarction and subsequent post-infarction heart failure are among the leading causes of mortality worldwide. The endocannabinoid system has emerged as an important modulator of cardiovascular disease, however the role of endocannabinoid metabolic enzymes in heart failure is still elusive. Herein, we investigated the endocannabinoids and their metabolic enzymes in ischemic end-stage failing human hearts and non-failing controls. METHODS AND RESULTS: Quantitative real-time PCR, targeted lipidomics, and activity-based protein profiling (ABPP) enabled assessment of the endocannabinoids and their metabolic enzymes in ischemic end-stage failing human hearts and non-failing controls. Based on lipidomic analysis, two subgroups were identified within the ischemic heart failure group; the first similar to control hearts and the second with decreased levels of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and drastically increased levels of the endocannabinoid anandamide (AEA), other N-acylethanolamines (NAEs) and free fatty acids. The altered lipid profile was accompanied by strong reductions in the activity of 13 hydrolases, including the 2-AG hydrolytic enzyme monoacylglycerol lipase (MGLL). CONCLUSIONS: Our findings suggest the presence of different biological states within the ischemic heart failure group, based on alterations in the lipid and hydrolase activity profiles. In addition, this study demonstrates that ABPP is a valuable tool to rapidly analyze enzyme activity in clinical samples with potential for novel drug and biomarker discovery. Published by Elsevier Ltd.
AIM: Acute myocardial infarction and subsequent post-infarction heart failure are among the leading causes of mortality worldwide. The endocannabinoid system has emerged as an important modulator of cardiovascular disease, however the role of endocannabinoid metabolic enzymes in heart failure is still elusive. Herein, we investigated the endocannabinoids and their metabolic enzymes in ischemic end-stage failing human hearts and non-failing controls. METHODS AND RESULTS: Quantitative real-time PCR, targeted lipidomics, and activity-based protein profiling (ABPP) enabled assessment of the endocannabinoids and their metabolic enzymes in ischemic end-stage failing human hearts and non-failing controls. Based on lipidomic analysis, two subgroups were identified within the ischemic heart failure group; the first similar to control hearts and the second with decreased levels of the endocannabinoid2-arachidonoyl-glycerol (2-AG) and drastically increased levels of the endocannabinoidanandamide (AEA), other N-acylethanolamines (NAEs) and free fatty acids. The altered lipid profile was accompanied by strong reductions in the activity of 13 hydrolases, including the 2-AG hydrolytic enzyme monoacylglycerol lipase (MGLL). CONCLUSIONS: Our findings suggest the presence of different biological states within the ischemic heart failure group, based on alterations in the lipid and hydrolase activity profiles. In addition, this study demonstrates that ABPP is a valuable tool to rapidly analyze enzyme activity in clinical samples with potential for novel drug and biomarker discovery. Published by Elsevier Ltd.
Entities:
Keywords:
Cardiac ischemia; Chemical proteomics; Endocannabinoid system; Lipidomics
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