Platelet-leukocyte Complex Formation is Associated with, but Dispensable for Myocardial Ischemia Reperfusion Injury

Scientific Research Question: P-selectin is an activatable adhesion molecule on platelets promoting platelet aggregation, and platelet-leukocyte complex (PLC) formation via PSGL-1 binding, respectively. Increased numbers of PLC circulate in patients with acute myocardial infarction and predict adverse outcome. Yet, their pathomechanistic significance remains unclear. In this work, we tested the relevance of P-selectin mediated PLC formation for leukocyte recruitment to sites of inflammation, and myocardial ischemia and reperfusion injury in mice.

Methodology: Bl6J mice were irradiated and reconstituted with either P-selectin deficient (KO) or wild type (WT) bone marrow cells. P-selectin expression in endothelial cells remained unaffected. Given that P-selectin was only expressed by platelets in the blood this approach allowed us to test the specific function of platelet-derived P-selectin.

Findings: Circulating PLC frequencies triple and peak within 24 hours of reperfusion following transient myocardial ischemia in mice. In KO chimeras, circulating platelet-leukocyte complexes were diminished by more than 70% following myocardial ischemia/reperfusion injury. Yet, leukocyte rolling and adhesion to the activated endothelium was similar in both groups, as was infiltration into sterile peritonitis. Likewise, myocardial infarct size, tissue inflammation and loss in cardiac function remained unaffected despite the lack of circulating and infiltrating PLC. In contrast, P-selectin on platelets supported the phagocytosis of E. coli and Staph. aureus bacterial particles by monocytes and neutrophils.

Conclusions: Conserved response patterns to danger signals released during myocardial ischemia and reperfusion activate platelets and lead to P-selectin dependent complex formation with leukocytes. These direct platelet-leukocyte interactions may have developed to support bacterial clearing, but they seem dispensable for inflammatory cell recruitment to the activated endothelium and healing after myocardial infarction. Our results suggest that increased numbers of circulating PLC are a mere marker rather than a mediator of cardiac damage.

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