Clopidogrel Prophylaxis Abates Myocardial Ischemic Injury and Inhibits the Hyperlipidemia-Inflammation Loop in Hypercholestrolemic Mice

Abstract

Platelet hyper adhesiveness orchestrates with inflammation and vascular muscle proliferation leading to atheroma formation and endothelial dysfunction. The current study aims to compare the prophylactic role of Aspirin and Clopidogrel therapy against isoproterenol-induced acute myocardial infarction (AMI), in mice on high-fat, cholesterol-rich diet (HFD-C). The animals received HFD-C with Aspirin or Clopidogrel for 8weeks and were subjected to AMI by isoproterenol. The blood lipids, inflammatory cytokines, myocardial enzymes, redox state, long pentraxin (PTX3), and matrix metalloproteinases (MMP-2 and MMP-9) activities were investigated. Antiplatelet therapy moderated the hyperlipidemia induced by HFD-C in the current study. Essentially, the total cholesterol and LDL-C levels were lower with Aspirin than with Clopidogrel therapy. Yet Aspirin and Clopidogrel each comparably lowered CK-MB, AST, MMP-2, MMP-9, and the lipid peroxidation product malondialdehyde (MDA) in the hyperlipidemic animals exposed to AMI. However, the decline in cTn-T, LDH and PTX3 levels was greater after Clopidogrel than Aspirin administration. Therefore, Clopidogrel provides greater protection against AMI than Aspirin in the hyperlipidemic mice. This could be explained by the suppression of the proinflammatory cytokines IL-6, TNF-α, TGF-1β and stabilization of the extracellular matrix through the inhibition of MMP-2 and MMP-9 activities. Furthermore, Clopidogrel demonstrated significant antioxidative action in the AMI animals, resulting in diminished MDA production and preserved CAT activity. Beside its therapeutic role in the thrombotic vascular events, Clopidogrel confers significant protection against ischemic myocardial injury by counteracting the platelet-mediated inflammation and oxidative stress associated with HFD-C consumption in animals.