Department of Anesthesiology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
Department of Pediatrics, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
PLoS One. 2020 Dec 31;15(12):e0244792. doi: 10.1371/journal.pone.0244792. eCollection 2020.
Blood coagulation is central to myocardial ischemia and reperfusion (IR) injury. Studies on the light elicited circadian rhythm protein Period 2 (PER2) using whole body Per2-/- mice found deficient platelet function and reduced clotting which would be expected to protect from myocardial IR-injury. In contrast, intense light induction of PER2 protected from myocardial IR-injury while Per2 deficiency was detrimental. Based on these conflicting data, we sought to evaluate the role of platelet specific PER2 in coagulation and myocardial ischemia and reperfusion injury. We demonstrated that platelets from mice with tissue-specific deletion of Per2 in the megakaryocyte lineage (Per2loxP/loxP-PF4-CRE) significantly clot faster than platelets from control mice. We further found increases in infarct sizes or plasma troponin levels in Per2loxP/loxP-PF4-CRE mice when compared to controls. As intense light increases PER2 protein in human tissues, we also performed translational studies and tested the effects of intense light therapy on coagulation in healthy human subjects. Our human studies revealed that intense light therapy repressed procoagulant pathways in human plasma samples and significantly reduced the clot rate. Based on these results we conclude that intense light elicited PER2 has an inhibitory function on platelet aggregation in mice. Further, we suggest intense light as a novel therapy to prevent or treat clotting in a clinical setting.
血液凝固是心肌缺血再灌注（IR）损伤的核心。使用全身 Per2-/- 小鼠研究光诱导的生物钟蛋白 Period 2（PER2）发现血小板功能缺陷和凝血减少，这可能有助于保护心肌免受 IR 损伤。相比之下，强烈的光诱导 PER2 可保护心肌免受 IR 损伤，而 Per2 缺乏则有害。基于这些相互矛盾的数据，我们试图评估血小板特异性 PER2 在凝血和心肌缺血再灌注损伤中的作用。我们证明，来自巨核细胞谱系中组织特异性敲除 Per2 的小鼠（Per2loxP/loxP-PF4-CRE）的血小板比对照小鼠的血小板凝结速度更快。我们还发现，与对照组相比，Per2loxP/loxP-PF4-CRE 小鼠的梗死面积或血浆肌钙蛋白水平增加。由于强烈的光照会增加人体组织中的 PER2 蛋白，我们还进行了转化研究，并测试了强烈光照疗法对健康人体凝血的影响。我们的人体研究表明，强烈的光照疗法抑制了人血浆样本中的促凝途径，并显著降低了凝血速度。基于这些结果，我们得出结论，强烈光照诱导的 PER2 对小鼠血小板聚集具有抑制作用。此外，我们建议将强烈光照作为一种新的治疗方法，以预防或治疗临床环境中的血栓形成。
