Reguliert Protein Arginine Deaminase 4 die Inflammasom-Aktivierung in Endothel-Zellen sowie Granulozyten und treibt dadurch den Myokardialen Ischämie-Reperfusionsschaden an?
Zusammenfassung der Projektergebnisse
Activation of inflammatory pathways and a persistent increase in inflammatory biomarkers are characteristic for heart failure with preserved ejection fraction (HFpEF) a critical public health problem increasing in prevalence. Inflammation-mediated HFpEF animal models are scarce. We show that the well-established model of collagen induced arthritis (CIA) in a DBA/1 strain is a viable option to emulate chronic inflammation on the pathway of chronic diastolic heart failure development. Mice with Collagen Induced Arthritis (CIA) undergo concentric hypertrophic myocardial remodeling, resulting in clinically evident diastolic dysfunction and heart failure as seen in clinical HFpEF. Our data point towards thromboinflammation as a key mechanism of HFpEF development in CIA with increased myocardial concentration of activated neutrophils, neutrophil extracellular traps (NETs) and increased Von Willebrand Factor (VWF) release/deposition in the myocardial vasculature. Selective inhibition of Protein Arginine Deiminase 4 (PAD4) an enzyme comprehensively involved in neutrophil activation and NET release with an orally available inhibitor (JBI-589) prevented the adverse hypertrophic myocardial remodeling with reduced neutrophil recruitment to the myocardium and reduced biomarkers of thromboinflammation. Our results support a propulsive effect of PAD4 on NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasom assembly and subsequent release of its effector enzyme Interleukin 1 beta (IL-1β ) in heart tissue with JBI-589-treatment significantly reducing levels of IL-1β in heart tissue of arthritic mice. This finding not only adds to the understanding of heart failure in chronic inflammatory diseases and the fundamental understanding of HFpEF pathology but also proposes PAD4 as possible target to prevent and/or treat heart failure in chronic inflammatory and autoimmune diseases.
Projektbezogene Publikationen (Auswahl)
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Complement system component dysregulation is a distinctive feature of COVID-19 disease: a prospective and comparative analysis of patients admitted to the emergency department for suspected COVID-19 disease. Journal of Thrombosis and Thrombolysis, 53(4), 788-797.
Gauchel, Nadine; Rieder, Marina; Krauel, Krystin; Goller, Isabella; Jeserich, Maren; Salzer, Ulrich; Venhoff, Ana Cecilia; Baldus, Niklas; Pollmeier, Luisa; Wirth, Luisa; Kern, Winfried; Rieg, Siegbert; Busch, Hans-Jörg; Hofmann, Maike; Bode, Christoph; Duerschmied, Daniel; Lother, Achim & Heger, Lukas A.
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Thromboinflammation: From Atherosclerosis to COVID-19. Arteriosclerosis, Thrombosis, and Vascular Biology, 42(9), 1103-1112.
Wagner, Denisa D. & Heger, Lukas A.
