OC 79.3 - Antiplatelet and anticoagulant (APAC) compound restricts thromboinflammation and maintains cardiac function following myocardial injury

Wednesday, June 26, 2024

10:45 – 11:00 ICT

Room: 209 A-D

Co-Author(s)

Sameen Fatima

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

Hamzah Khawaja

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Leipzig, Germany
Leipzig, Sachsen, Germany
Saira Ambreen, phd

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

Anubhuti Gupta

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

Junior Group Leader
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Leipzig, Germany
Leipzig, Sachsen, Germany
Ahmed Elwakiel

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

Annukka Jouppila

Technical Assistant
Aplagon Ltd., Helsinki, Finland
Helsinki, Keski-Suomi, Finland
Riitta Lassila, MD, PhD

Professor of Coagulation Medicine
Department of Hematology, Coagulation Disorders Unit, and Research Program Unit in Systems Oncology Oncosys, Medical Faculty, University of Helsinki, Finland
Helsinki, Uusimaa, Finland
Berend Isermann, Prof. Dr. med.

Director
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Leipzig, Germany
virtuell, Sachsen, Germany

Presenting Author(s)

Khurrum Shahzad

PostDoc
University of Leipzig
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. APAC is a heparin proteoglycan mimic conveying both antiplatelet and anticoagulant (APAC) functions.

Aims: Given that both platelet- and coagulation activation are intimately associated with inflammation, we speculated that APAC ameliorates thromboinflammation and myocardial injury 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 (0.5µg/kg, intravenously). 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 plasma TAT (thrombin-antithrombin) and PF4 (platelet factor 4) and reduced infarct size. Mechanistic studies revealed that APAC restricts NLRP3 inflammasome activation (NLRP3, cleaved caspase-1 and cleaved IL [interleukin]-1β) and NET (neutrophil extracellular trap) formation (CitH3, MPO, PAD4), which are known to convey pathogenic roles in myocardial IRI. Congruently APAC prevented inflammatory cell infiltration into injured heart tissue and restricted the expression of proinflammatory cytokines IL-6 and TNFα (tumor necrosis factor alpha). The constitutively active Nlrp3A350V mutation abolished the protective effect of APAC, demonstrating that NLRP3 suppression is involved in APAC-mediated protection from myocardial IRI. APAC treatment post myocardial IRI likewise reduced infarct size and myocardial NLRP3 inflammasome activation. APAC’s anti-inflammatory effect was associated with reduced myocardial fibrosis 28 days post–myocardial IRI und improved LV ejection fraction, cardiac output and stroke volume, reflecting improved cardiac function.

Conclusion(s): These studies reveal that both pre- and post-treatment with APAC restricts NLRP3 inflammasome activation and NETs formation in myocardial IRI, thus ameliorating myocardial injury.