Type I phosphoinositide 3-kinases: potential antithrombotic targets?

Arterial thrombosis is the single most common cause of death and disability in industrialized societies and is the primary pathogenic mechanism underlying acute myocardial infarction and ischemic stroke. Platelets play a central role in this process, and as a consequence, a great deal of effort has gone into identifying the mechanisms regulating the adhesive function of platelets. Platelet adhesion is controlled by intracellular signaling pathways, with growing evidence for a major role for phosphoinositide 3-kinases (PI3Ks) in this process. Platelets express all type I PI3K isoforms, including p110alpha, p110beta, p110delta and p110gamma, with recent evidence suggesting important roles for p110gamma and p110beta in regulating distinct phases of the platelet activation process. Deficiency of p110 gamma or inhibition of p110beta produces a marked defect in arterial thrombosis without a corresponding increase in bleeding time, raising the possibility that inhibition of one or more PI3K isoforms may represent an effective antithrombotic approach.

Degradative pathways in cultured synovial fibroblasts: selective effects of pulsed electromagnetic fields.

A cell culture model for studying the cytokine-mediated degradation of connective tissue was exposed to clinically applied, low-frequency pulsed electromagnetic fields (PEMF), and levels of collagenolytic activity, two lysosomal hydrolases, and prostaglandin E2 were measured. PEMFs reduced the release of two lysosomal enzymes by cultured rabbit synovial fibroblasts but did not affect their response to mononuclear-cell-conditioned medium. PEMF did not alter levels of cytokine activity produced by a mixed mononuclear cell population, nor did they affect the cytokine-mediated release of collagenase or prostaglandin E2 by synovial fibroblasts. The relevance of these findings to the clinical application of PEMF to soft- and hard-tissue injuries is discussed.