The Role of ROCK in Platelet-Monocyte Collaborative Induction of Thromboinflammation during Acute Coronary Syndrome

Background Arterial thrombosis is initiated by atherosclerotic plaque damage, prothrombotic material release and platelet aggregation. Platelets are primary mediators involved in thrombosis and cooperate with vascular and immune cells. Objective Herein, we investigated how activated platelets interacted with monocytes in atherothrombosis. Methods and Results We collected patients' blood from coronary arteries during percutaneous coronary intervention and measured platelet activity. Platelets from coronary arteries had higher pseudopodium expression and activity in patients with acute coronary syndrome (ACS). Ribosome profiling of platelets from coronary blood mapped a vigorous upregulation of Rho GTPases and their downstream effectors. RhoA activated downstream Rho-associated coiled-coil containing protein kinase (ROCK), and ROCK increased surface P-selectin in coronary blood platelets. The interaction between platelets and monocytes was observed in vitro, and was found in ruptured coronary plaques of ACS. Further we found that activated platelets promoted monocytes transmigration, which could be suppressed in the presence of ROCK inhibitors. The increased surface P-selectin on thrombin-induced platelets interacted with monocytes to upregulate monocyte chemokine receptor 2 (CCR2) expression via the ROCK pathway. The expression of CCR2 was higher in monocyte-platelet aggregates than in monocytes without platelets. Finally, using the Asian Screening Array BeadChip, we identified single-nucleotide polymorphism (SNP) associated with cardiovascular events. Notably, patients having homozygous major alleles of the RHOA SNP rs11706370 presented with higher risks of cardiovascular events. Conclusion Through ROCK-activated cytoskeleton remodeling and P-selectin expression, platelets were recruited and interacted synergistically with high CCR2-expressing monocytes to induce thromboinflammation in atherothrombosis.