Protein S Confers Neuronal Protection During Ischemic/Hypoxic Injury in Mice

Abstract

Background-Protein S is an antithrombotic factor that also exhibits mitogenic activity. Thus, we hypothesized that protein S may control cerebrovascular thrombosis in stroke and protect brain tissue from ischemic injury. Methods and Results-We studied protein S in a murine in vivo model of stroke and an in vitro model of neuronal hypoxia/reoxygenation injury. Animals received purified human plasma-derived protein S or vehicle intravenously 10 minutes after initiation of middle cerebral artery occlusion followed by reperfusion. Protein S at 0.2 to 2 mg/kg significantly improved the motor neurological deficit by 3.8-to 3.2-fold and reduced infarction and edema volumes by 45% to 54% and 45% to 62%, respectively. Protein S at 2 mg/kg improved postischemic cerebral blood flow by 21% to 26% and reduced brain fibrin deposition and infiltration with neutrophils by 40% and 53%, respectively. Intracerebral bleeding was not observed with protein S. Protein S protected ischemic neurons in vivo and cultured neurons from hypoxia/reoxygenation-induced apoptosis in a time-and dose-dependent manner. Recombinant human protein S exerted protective effects from hypoxia-induced damage similar to the plasma-derived protein S both in vivo and in vitro. Conclusions-Protein S is a significant neuroprotectant during ischemic brain injury with direct effects on neurons and antithrombotic effects. Thus, protein S could be a prototype of a new class of agents for clinical stroke with combined direct neuronal protective effects and systemic antithrombotic and antiinflammatory activities.

Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age

“…Endothelial injury as a trigger of thrombosis may be enhanced by a preexisting defect in protein S synthesis at the site of injury. Furthermore, some cytoprotective effects also have been attributed to protein S. 30,31 Since its first description, 9 the amount of data indicating a link between VTE and subsequent ATE has been increasing. 10 In our study, subjects with prior VTE had a risk for ATE similar to that of subjects without prior VTE.…”

Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S–C4b binding protein complex

“…The reported mitogenic activity of PS toward vascular smooth muscle cells 170 will also have to be re-examined in the light of the finding that PS exerts a neuroprotective effect in murine models. 62 Indeed, the latter observation suggests a possible role of PS as a therapeutic agent with combined anticoagulant and cell protective effects. It is intriguing to speculate how the neuroprotective effects might be modulated by complex formation with C4BP␤ϩ.…”

“…107 In addition, PS has been shown to reduce the number of cortical neurons in which apoptosis is induced after hypoxia/reoxygenation injury by approximately 70%. 62 It seems likely that PS would bind to these cells during apoptosis, via the same mechanism, although this was not examined directly.…”

Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway

“…Interestingly, in the same mouse model of stroke, the administration of protein S was likewise found to provide neuroprotection, the mechanism of action for which is unknown. 86 There are many unresolved questions related to the APCmediated effects on PAR-1 in vivo, eg, it is difficult to understand the relationships between the APC-mediated and thrombin-mediated cleavages of PAR-1 and their physiological roles. The recent demonstration of thrombin being several orders of magnitude (10 4 ) more potent than APC in cleaving PAR-1 will stimulate research aiming at elucidation of the physiological significance of the APC-mediated PAR-1 cleavage in vivo.…”