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• W2512392810 abstract "Abstract Introduction Platelet activation results in a loss of membrane phospholipid asymmetry with concomitant exposure of procoagulant phosphatidylserine (PS) at the outer leaflet of membrane bilayer. PS provides binding sites for the assembly of prothrombinase and the tenase complex on activated platelets. In spite of its central role in thrombosis and hemostasis, the signal transduction mechanisms leading to PS exposure are not well characterized. Previously, we have shown that ROCK inhibitor, Y-27632, induces increased PS exposure following activation of platelets. However, Y-27632 does not distinguish between ROCK-1 and ROCK-2. Here, we studied activation induced PS exposure in ROCK-1 deficient platelets. Methods Platelets were isolated from ROCK-1 deficient and control mice. PS expression was measured on a flow cytometer using FITC-lactadherin (5 μg/ml). Platelet aggregation was carried out by standard turbidometric methods. Platelet procoagulant activity was measured in a prothrombinase assay consisting of prothrombin (1μM), factor Va (10 nM), factor Xa (10 pM), calcium (1.5 mM), collagen (10 μg/ml), and platelets (1x106/ml). Thrombin formation was determined by measuring absorbance at 405 nm in a microplate reader Calcium mobilization was measured by incubating ROCK-1 and WT platelets with Fura 2 AM and measuring the Fura 2 fluorescence after collagen treatment. An in vivo light/dye-induced endothelial injury/thrombosis model was used to assess the occlusion in cremasteric venules of mice. Phosphorylation status was measured by Western blot analysis of platelet lysate before and after activation. Results Collagen induced significantly more PS exposure in ROCK-1 deficient platelets compared to platelets from wild type littermates. ROCK-1 deficient platelets are more procoagulant as it generates more thrombin compared to control platelets. ROCK-1 deficient mice have a shorter occlusion time in a light/dye induced endothelial injury/thrombosis model in cremasteric venules compared to its littermates (3.16 ± 1.33 min versus 6.6 ± 2.6 min; p = 0.01). Since PS exposure is associated with increase in cytosolic calcium level, we measured calcium concentration in WT and ROCK-1 deficient platelets following collagen stimulation. There was no significant difference in calcium levels in collagen stimulated ROCK-1 and WT platelets. Hence, it is unlikely that the increased PS exposure in ROCK-1 deficient platelets is due to changes in calcium mobilization. Besides calcium, actin cytoskeleton rearrangement also plays a major role in PS exposure. ROCK1 modulates cytoskeleton rearrangement is through LIM kinase-1 (LMK-1). ROCK-1 mediated activation of LIMK-1 catalyses phosphorylation of cofilin-1, an actin severing protein. Phosphorylation inactivates actin severing activity of cofilin-1. Hence, ROCK-1 deficiency should lead to activation of cofilin-1. Indeed, collagen stimulated ROCK-1 deficient platelets showed a major reduction in phosphorylation of cofilin-1. Increased activity of cofilin-1 in ROCK-1 deficient platelets is further supported by the fact that F- actin content is significantly reduced in ROCK-1 deficient platelets. Conclusion We postulate that cofilin-1-induced F-actin severing and subsequent cytoskeletal rearrangement plays an important role in collagen-induced PS exposure in platelets. Disclosures: No relevant conflicts of interest to declare." @default.
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• W2512392810 date "2013-11-15" @default.
• W2512392810 modified "2023-09-28" @default.
• W2512392810 title "Rho Associated Coiled-Coil Kinase-1 Regulates Collagen-Induced Phosphatidylserine Exposure In Platelets" @default.
• W2512392810 doi "https://doi.org/10.1182/blood.v122.21.3509.3509" @default.
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