Activated platelets contribute importantly to myocardial reperfusion injury

Abstract

Platelets become activated during myocardial infarction (MI), but the direct contribution of activated platelets to myocardial reperfusion injury in vivo has yet to be reported. We tested the hypothesis that activated platelets contribute importantly to reperfusion injury during MI in mice. After 30 min of ischemia and 60 min of reperfusion, P-selectin knockout mice had a significantly smaller infarct size than that of wild-type mice (P < 0.05). Platelets were detected by P-selectin antibody in the previously ischemic region of wild-type mice as early as 2 min postreperfusion after 45 min, but not 20 min, of ischemia. The appearance of neutrophils in the heart was delayed when compared with platelets. Flow cytometry showed that the number of activated platelets more than doubled after 45 min of ischemia when compared with 20 min of ischemia or sham treatment (P < 0.05). Platelet-rich or platelet-poor plasma was then transfused from either sham-operated or infarcted mice after 45 and 10 min of ischemia-reperfusion to mice undergoing 20 and 60 min of ischemia-reperfusion. Infarct size was increased by threefold and platelet accumulation was remarkably enhanced in mice treated with wild-type, MI-activated platelet-rich plasma but not in mice receiving either platelet-poor plasma from wild types or MI-activated platelet-rich plasma from P-selectin knockout mice. In conclusion, circulating platelets become activated early during reperfusion and their activation depends on the duration of the preceding coronary occlusion and is proportional to the extent of myocardial injury. Activated platelets play an important role in the process of myocardial ischemia-reperfusion injury, and platelet-derived P-selectin is a critical mediator.

Diminished thrombus formation and alleviation of myocardial infarction and reperfusion injury through antibody- or small-molecule-mediated inhibition of selectin-dependent platelet functions

“…Data are presented as mean ± SEM. This figure corresponds to supplemental videos 4-6. denominators in a number of complex platelet-related cardiovascular diseases, 11,13,17,18,41,42 thus providing a rationale for modulating P-selectin functions in order to treat and/or prevent such disorders. P-selectin expressed by activated endothelial cells may also contribute to disease processes.…”

“…Several cell types as well as an intertwined network of soluble mediators and adhesion molecules orchestrate this process. 41 However, given that several lines of evidence indicate that platelets play an important role in reperfusion injury, 13 modulating selectin-dependent functions of platelets and other cells may enhance myocardial salvage in patients with myocardial infarction. 52 Although all three selectins are thought to be involved in ischemia and reperfusion injury, P-selectin appears to play a major role since it is upregulated within minutes following a stimulatory event.…”

“…[10][11][12] Based upon comparisons between P-selectin-deficient and wild-type mice, it has recently been suggested that P-selectin expressed on activated platelets contributes to myocardial reperfusion injury. 13 However, the exact role of P-selectin in these processes is not clear, and its use as a therapeutic target structure has not been established. P-selectin expressed by endothelial cells is rapidly translocated to the cell membrane upon activation and may also contribute to aggregate formation.…”

Cardioprotection—Time to Take Into Account Clinical Complexity: The Case of Antiplatelet Agents

“…This benefit is most likely mediated through the effect of the drugs on platelets, which could limit IR injury. The drugs could prevent platelet activation [16] and release of deleterious cytokines, which otherwise could have enhanced inflammation [17] or activated other cell types including …”

“…This benefit is most likely mediated through the effect of the drugs on platelets, which could limit IR injury. The drugs could prevent platelet activation [16] and release of deleterious cytokines, which otherwise could have enhanced inflammation [17] or activated other cell types including leukocytes [18], endothelial cells [19] or microparticles [20]. Interestingly, the OM2 antibody offered a promising therapeutic window with an efficient anti-platelet effect and a smaller bleeding risk, when compared to cangrelor.…”