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±0.8×10 4 /vessel versus 2.3±1.2×10 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.

Awareness, treatment, control, and determinants of dyslipidemia among adults in China

“…The survey is conducted annually as a stroke surveillance program in the country. Details have been described elsewhere 14 . In brief, the survey involved Chinese adults aged 40 years or more.…”

“…This cluster sampling method was implemented in each primary sampling unit. All individuals aged 40 years or above were recruited during the primary screening 14 . About 180,000 participants were randomly selected for further assessment for stroke risk factors such as dyslipidemia.…”

Losartan and azelastine either alone or in combination as modulators for endothelial dysfunction and platelets activation in diabetic hyperlipidemic rats

“…[ 56 ] Such Inhibition can significantly decrease the vascular levels of NADPH oxidase subunits like NOX‐1, 2 and 4, along with decreased macrophages infiltration in the aorta in response to Ang II. [ 57 ] AT1 receptors are usually expressed on platelets surface [ 58 ] and blockage of these receptors in mice vessels resulted in reduced P‐selectin expression on platelets along with inhibition of platelet adhesion. [ 54 ] Generally, the platelet activation model is dependent mainly on endothelial cell [ 59 ] and damage of endothelial cells by Ang II might further induce platelet activation.…”

A link between inflammation and thrombosis in atherosclerotic cardiovascular diseases: Clinical and therapeutic implications

“…Confirmation has been provided by atherosclerotic animal studies in LDL receptor-deficient mice, documenting decreased levels of pro-inflammatory cytokines ultimately leading to reduced NF-κB activity and enhanced atherosclerotic plaque stability after acetylsalicylic acid treatment [85]. Furthermore, P2Y 12 inhibitors have been found to act in a similar fashion, as expressed by the lower levels of P-Selectin, CD40 ligand and TF in animal models of myocardial infarction after treatment with clopidogrel as well as in animal (wild-type male mice and male New Zealand white rabbits) models of Angiotensin-II-induced platelet aggregation [86,87]. This anti-inflammatory action appears to stem from various cellular and molecular mechanisms (Fig.…”