Stopping STIM Stops Strokes

Science Signaling  15 Jul 2008:
Vol. 1, Issue 28, pp. ec259
DOI: 10.1126/scisignal.128ec259

Proper responses of platelets in the blood to various physiological signals are essential: Unresponsiveness prevents clotting at sites of wounds, but overactivity can contribute to heart attacks or stroke. Platelets respond to a number of factors, but the various signals all feed into activation of phospholipase C and consequent release of calcium from intracellular stores. Depletion of calcium from the intracellular stores then leads to influx of extracellular calcium. The STIM1 protein (stromal interaction molecule 1) functions in detection of store emptying and activation of store-operated channels that allow calcium entry. Varga-Szabo et al. used knockout mice in which the Stim 1 gene was disrupted to study the role of STIM1 in arterial thrombosis and ischemic brain infarction. The Stim 1–/– animals died a few hours after birth, but the authors were able to transplant bone marrow from the knockout animals to lethally irradiated host mice to study platelet function. In two in vivo models of arterial thrombosis induced by injury, formation of occlusive thrombi was inhibited in the Stim 1–/– animals. Similarly, in a model of ischemic brain infarction induced by restriction of blood flow through the middle cerebral artery, infarct size was reduced in the Stim 1–/– animals. Most animals with the Stim 1–/– platelets stopped bleeding from a wound at the tail tip within about 10 minutes, as did wild-type mice. The response was more variable in the Stim 1–/– animals, however, and about 35% of the animals showed longer bleeding. Because of this relatively mild effect on bleeding, the authors propose that inhibitors of Stim 1 might be attractive as antithrombolitics that could help treat stroke patients without the unacceptable side effect of increased intracerebral hemorrhage. As a caveat, the authors do note that results in the mouse models may not necessarily be directly comparable to the situation in humans.

D. Varga-Szabo, A. Braun, C. Kleinschnitz, M. Bender, I. Pleines, M. Pham, T. Renné, G. Stoll, B. Nieswandt, The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J. Exp. Med. 205, 1583-1591 (2008). [Abstract] [Full Text]