OC 62.2 - Antiplatelet and anticoagulant compound (APAC) restricts thromboinflammation to ameliorates myocardial ischemia reperfusion injury

Tuesday, June 27, 2023

15:00 – 15:15 ET

Room: 710B

Session Available As: On-Demand

Co-Author(s)

Sameen Fatima, MPhil

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
SA

Saira Ambreen

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
Shrey Kohli, PhD

Group leader
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
Riitta Lassila, MD, PhD (she/her/hers)

Professor of Coagulation Medicine
Helsinki University Hospital, Coagulation Disorders Unit, Department of Haematology, Comprehensive Cancer Centre, and Research Program Unit in System Oncology, University of Helsinki, Helsinki, Finland
Helsinki, Uusimaa, Finland
Berend Isermann, PhD MD (he/him/his)

Institute director
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany

Presenting Author(s)

Khurrum Shahzad

Group leader
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany

Background: 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.

Aims: We speculate that a novel compound conveying both antiplatelet and anticoagulant (APAC) functions may ameliorate thromboinflammation triggered by myocardial IRI.

Methods: 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 (0.5mg/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.

Results: 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.

Conclusion(s): 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.

Learning Objectives:

Antiplatelet and anticoagulant compound (APAC) prevents from myocardial ischemia reperfusion injury in mice
APAC pre and post-treatment restricts thromboinflammation following myocardial ischemia reperfusion injury
APAC blunt NLRP3 inflammasome activation following myocardial ischemia reperfusion injury