Inhibition of platelets by clopidogrel suppressed ang II-induced vascular inflammation, oxidative stress, and remodeling

Abstract

Background—Platelets play a role in promoting inflammatory responses under several disease conditions. Platelets are activated in hypertensive patients. However, the mechanisms responsible for platelet-mediating vascular inflammation are unknown. The present study investigated the role of platelets in promoting vascular inflammation following angiotensin II (Ang II) stimulation, and the efficacy of antiplatelet intervention. Methods and Results—Within a mouse model of Ang II infusion (490 ng/kg per min), we measured the portion of P-selectin– positive platelets and platelet-monocyte (P-M) binding in blood samples, and platelet accumulation and P-M binding in vessels under Ang II stimulation at days 1, 3, and 7. We tested the efficacy of clopidogrel (15 mg/kg per day, followed by 5 mg/kg per day) on Ang II-induced platelet activation, P-M binding, vascular platelet accumulation, as well as vascular inflammation and remodeling at day 7 or 14. Clopidogrel reduced platelet vascular deposition (28.7±2.4% versus 18.3±2.9%), suppressed inflammatory cell infiltration (3.6±0.8910×4/vessel versus 2.3±1.2910×4/vessel) and oxidative stress, and attenuated vascular remodeling and dysfunction (55.0±5.5% versus 84.0±6.0%) following Ang II stimulation at day 7 or 14. Clopidogrel suppressed Ang II-induced P-M binding both at circulating (13.4±3.3% versus 5.9±2.7%) and regional (33.4±4.3% versus 11.9±2.7%) levels. Conclusions—Platelets play a critical role in vascular inflammation under Ang II stimulation, with a marked promotion of P-M binding as an important mechanism. Clopidogrel prevented vascular inflammation in Ang II-infused mice.