Abstract
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.
Highlights
The role of platelets in the thrombotic occlusion of coronary vessels leading to myocardial ischemia is well understood [1,2,3]
Platelet counts in Per2loxP/loxP-platelet factor 4 (PF4)-CRE mice are unchanged
As studies in Per2 whole-body knockout mice found reduced platelet counts when compared to controls, we first analyzed platelet numbers and mean platelet volume in blood samples from Per2loxP/loxPPF4-CRE and PF4-CRE mice
Summary
The role of platelets in the thrombotic occlusion of coronary vessels leading to myocardial ischemia is well understood [1,2,3]. The early morning surge in blood pressure is accompanied by endothelial dysfunction, a peak in clinical thrombosis, and adverse cardiovascular events [4, 5]. These events correspond to oscillations in circadian gene and protein expressions, implicating a critical role of the circadian clock in these processes [6,7,8,9]. Photic stimuli are transmitted from the retina to target neurons in the brain, where
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