mk-0524 and Thrombosis

Atherosclerosis is a chronic inflammatory disease affecting medium and large arteries resulting from a complex interaction between genetic and environmental risk factors that include dyslipidemia, hypertension, diabetes mellitus, and smoking. The most serious manifestations of atherosclerotic vascular disease, such as unstable angina, myocardial infarction, ischemic stroke, and sudden death, largely result from thrombosis superimposed on a disrupted (ruptured or eroded) atherosclerotic plaque. Adoption and maintenance of a healthy lifestyle coupled with management of modifiable risk factors significantly reduce the adverse clinical consequences of athero-thrombosis. Reducing low-density lipoprotein cholesterol levels using statins and other agents serves as the primary pharmacologic approach to stabilize atherosclerotic vascular disease. However, a large residual risk remains, prompting the search for additional therapies for atherosclerosis management, such as raising atheroprotective high-density lipoprotein (HDL) and/or improving HDL function. This review focuses on new and emerging HDL-based therapeutic strategies targeting atherosclerosis.

Topics: Animals; Apolipoproteins; Atherosclerosis; Dyslipidemias; Endothelium, Vascular; Fibric Acids; Fibrinolysis; Gene Transfer Techniques; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipoproteins, HDL; Lipoproteins, LDL; Niacin; Oxidation-Reduction; Risk Factors; Thrombosis

The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D(2). Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD(2), which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. In fact, we found that in vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD(2) on platelet function, i.e. platelet aggregation, Ca(2+) flux, P-selectin expression, activation of glycoprotein IIb/IIIa and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations, laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and E-type prostanoid (EP)-3 receptor stimulation, as demonstrated in assays of platelet aggregation, Ca(2+) flux, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition of platelet function exerted by EP4 or I-type prostanoid (IP) receptors was not affected by laropiprant. These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have a beneficial profile with respect to platelet function and thrombotic events in vascular disease.

Topics: Blood Coagulation; Blood Platelets; Calcium; Dyslipidemias; Female; Gene Expression Regulation; Humans; Hypolipidemic Agents; Indoles; Male; Niacin; P-Selectin; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Prostaglandin D2; Receptors, Prostaglandin E, EP3 Subtype; Thrombosis