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

Abstract

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.

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

“…Serotonin is stored in dense granules, which is a key mediator of VSMC proliferation and is increased in platelets of PH patients with increased ROCK activity [ 185 ]. ROCK mediates the release of PDGF and P-selectin from the α-granules of activated platelets, which induces VSMC hyperplasia and monocyte transendothelial migration, respectively [ 180 , 181 , 186 ]. Hence, the inhibition of ROCK by Y-27632 diminishes superoxide production by NADPH oxidase in human platelets activated by agonists of PAR or the thromboxane receptor [ 180 ] and may interfere with endothelial cell function by reducing oxidative stress and increasing NO bioavailability.…”

Genetic risk model for in-stent restenosis of second-and third-generation drug-eluting stents

“…The study protocol for clinical demographic data and genomic data collection was registered to clinicaltrials.org ( http://clinicaltrials.gov/ct2/show/NCT03877614 ). ( Hsu et al., 2020 ) Patients in the NCKUH CAD cohort who were greater than or equal to 20 years old and underwent next-generation DES insertion at de novo coronary artery stenotic lesions in the NCKUH cardiac catheterization lab were eligible for this study. Only those patients having the willingness to participate in this genomic research and providing the written informed consent were enrolled in this study.…”

Higher premature atrial complex burden from the Holter examination predicts poor cardiovascular outcome

“…We conducted a retrospective cohort study by using Cardiovascular Disease Databank from National Cheng-Kung University Hospital 19 – 21 to enroll consecutive patients who had ever undergone 24-h Holter monitoring. Our databank contained the complete electronic medical records of patients who had been admitted to our cardiovascular ward/coronary care unit and had been followed up at cardiovascular outpatient department, or had undergone cardiovascular studies, including echocardiography, 24-h Holter monitoring, treadmill exercise test, thallium scan, peripheral or coronary angiography with/without intervention, electrocardiography with/without ablation, or device therapy.…”

“…All patients were asked to follow their daily routines without any limitation during the recording period. We used DR200/HE Holter 21 – 23 (NorthEast Monitoring, Inc., Maynard, MA USA) with a frequency response of 0.05 to 70 Hz in 180 samples/sec mode. We used 7-lead placement to acquire three-channel information: V5 (−, right manubrium; +, left anterior axillary line on the 5th rib), V1 (−, left of the manubrium; +, 2 cm right of the xiphoid process), and lead III (−, centered on the manubrium; +, left of the mid-clavicular line on the 5th rib).…”