Abstract 12855: ROCK2 in Platelets Mediates Platelet Aggregation and Adhesion, but Not Atherogenesis: Implications for Atherothrombosis
Background: The activation of platelets is the final common pathway for most acute vascular occlusive disease including atherothrombosis. However, the precise role of platelets in the development of atherosclerosis is unknown. Rho kinases (ROCKs)are important mediators of the actin cytoskeleton and have been implicated in atherosclerosis and vascular inflammation. Therefore, we hypothesize that platelet ROCKs may play an important role in atherogenesis and thrombus formation.
Methods and Results: Platelets from global ROCK2-deficient (ROCK2-/-) miceshowed decreased thrombin-induced pseudopodia formation, collagen adhesion, and aggregation compared with platelets from wild-type (WT) mice. To determine whether these ROCK2-mediated functions in platelets could affect atherogenesis, we generated a mouse strain with platelet-specific ROCK2 deficiency (ROCK2Plt-/-) using conditional ROCK2flox/flox mice and platelet-specific PF4-Cre mice. ROCK2Plt-/-mice were born at expected Mendelian ratios and did not show any phenotypic abnormalities. Furthermore, platelet count in ROCK2Plt-/- mice were comparable to control or WT mice. When bone marrow transplantation (BMT) was performed on control and ROCK2Plt-/- mice into recipient LDLr-/- mice, the resultant ROCK2Plt-/- BMT mice on high cholesterol diet showed no significant difference in en face lesions (12.3 ±4.56% vs. 11.7±3.07, n=10 in each group) or aortic sinus lesion areas compared to control BMT mice. However, compared to control BMT mice, ROCK2Plt-/-BMT mice exhibited prolonged bleeding time (578 ± 207 secvs. 346 ± 203 secP=0.0008), and washed platelets from ROCK2Plt-/- BMT miceshowed 80% decrease in aggregation to thrombin receptor-activating peptides (TRAP), but not to collagen. Furthermore, heterotypic aggregation between platelets and neutrophils in response to TRAP was reduced in ROCK2Plt-/- BMT mice compared to WT BMT mice.
Conclusion: These findings indicate that platelet ROCK2 mediates platelet aggregation and adhesion, but does not play an important role in the development of atherosclerosis. These results suggest that inhibition of ROCK2 in platelets may have beneficial effects in preventing atherothrombosis, but not atherogenesis.
- © 2011 by American Heart Association, Inc.