Nikola Sladojevic, Goo Taeg Oh, Hyung-Hwan Kim, Lea M Beaulieu, Hervé Falet, Karol Kaminski, Jane E Freedman, James K Liao
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引用次数: 21
Abstract
Aims: Rho-associated coiled-coil containing kinase (ROCK)-2 is an important mediator of the actin cytoskeleton. Because changes in the actin cytoskeleton are critical for platelet function, we hypothesized that ROCK2 in platelets will play important role in thrombosis and can be potentially a target for therapeutic intervention in thromboembolic stroke.
Methods and results: We generated platelet-specific ROCK2-deficient mice (ROCK2Plt-/-) from conditional ROCK2fl°x/fl°x and platelet factor (PF)-4-Cre transgenic mice. Platelets from ROCK2Plt-/- mice were less responsive to thrombin stimulation in terms of pseudopodia formation, collagen adhesion, and in the formation of homotypic and heterotypic aggregates. This corresponded to prolonged bleeding time and delayed vascular occlusion following vessel injury. To determine whether these changes in platelet function could affect thrombotic disease, we utilized a clot-embolic model of ischaemic stroke. When pre-formed clots from ROCK2Plt-/- mice were injected into the middle cerebral artery of control mice, cerebral blood flow recovery occurred more rapidly, leading to decreased cerebral injury and neurological deficits, compared to pre-formed clots from control mice. Interestingly, pre-formed clots from control mice produced similar degree of cerebral injury when injected into control or ROCK2Plt-/- mice, suggesting that platelet ROCK2 deficiency affects clot formation but not propagation. Indeed, in a non-thrombotic intra-filament MCA occlusion model of stroke, platelet ROCK2 deletion was not protective. Furthermore, ROCK2Plt-/- mice exhibit similar atherosclerosis severity and vascular remodeling as control mice.
Conclusion: These findings indicate that platelet ROCK2 plays important role in platelet function and thrombosis, but does not contribute to the pathogenesis of atherosclerosis and vascular remodeling.
期刊介绍:
Cardiovascular Research
Journal Overview:
International journal of the European Society of Cardiology
Focuses on basic and translational research in cardiology and cardiovascular biology
Aims to enhance insight into cardiovascular disease mechanisms and innovation prospects
Submission Criteria:
Welcomes papers covering molecular, sub-cellular, cellular, organ, and organism levels
Accepts clinical proof-of-concept and translational studies
Manuscripts expected to provide significant contribution to cardiovascular biology and diseases