1Universitätsklinikum Leipzig Klinik und Poliklinik für Kardiologie Leipzig, Deutschland; 2Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics Leipzig University, Leipzig, Germany Leipzig, Deutschland; 3Universitätsklinikum Leipzig Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik Leipzig, Deutschland
Myocardial ischemia-reperfusion injury (IRI) is hallmarked by thromboinflammation and both thrombotic and inflammatory effects contribute to acute organ damage. Therapies which not only target coagulation but simultaneously convey cytoprotective effects by dampening inflammatory mechanisms are expected to provide clinical benefits. We speculate that a novel compound conveying both antiplatelet and anticoagulant (APAC) functions may ameliorate thromboinflammation triggered by myocardial IRI. WT mice were either pretreated (60 minutes before LAD ligation) or post-treated (60 minutes after LAD ligation) with APAC, a heparin proteoglycan mimic with antiplatelet and anticoagulant effects (0.5µg/kg, intravenously) or PBS (control). Myocardial ischemia-reperfusion injury (IRI) was induced via LAD ligation (90 min ischemia followed by 24 h of reperfusion). We determined infarct size and blood and myocardial levels of thrombo-inflammatory markers. APAC pretreatment efficiently inhibited coagulation and platelet activation, as reflected by reduced TAT (thrombin-antithrombin) and PF4 (platelet factor 4) plasma levels. APAC treatment before myocardial IRI reduced infarct size. Mechanistic studies revealed that APAC restricts NLRP3 inflammasome activation (NLRP3, cleaved caspase-1 and cleaved IL [interleukin]-1β), which is known to convey a pathogenic in myocardial. Congruently APAC prevented inflammatory cell infiltration into injured heart tissue and restricted the expression of proinflammatory cytokines IL-1β, IL-6, and TNFα (tumor necrosis factor alpha). Importantly APAC treatment post myocardial IRI likewise reduced infarct size and myocardial NLRP3 inflammasome activation. These studies reveal that both pre- and post-treatment with APAC protects from myocardial IRI by restricting NLRP3 inflammasome activation. Thus APAC targets thromboinflammation in myocardial IRI and hence may be a feasible therapeutic approach to combat myocardial injury.