High‐density lipoproteins, platelets and the pathogenesis of atherosclerosis

Abstract

1. Prospective and interventional studies demonstrate an inverse relationship between plasma high-density lipoprotein (HDL)-cholesterol and the incidence of coronary artery disease. Although the atheroprotective effects of HDL are usually attributed to the reverse cholesterol transport, in which HDL shuttles cholesterol from cells in the arterial wall to the liver, other mechanisms are also under investigation. 2. Platelets are involved in both the initiation and progression of atherosclerotic lesions. In addition, the formation of thrombi over ruptured atherosclerotic plaques results in the narrowing or complete occlusion of coronary arteries. Current experimental evidence suggests that HDL may exert antiplatelet effects and thereby counteract the development of atherothrombotic vascular disease. 3. In vitro studies show that HDL inhibits agonist-stimulated platelet aggregation, fibrinogen binding, granule secretion and liberation of thromboxane A(2). Inhibitory effects of HDL are mediated, in part, by scavenger receptor type B1 and/or the apolipoprotein E receptor apoER2/LRP8 and are linked to the induction of intracellular signalling cascades encompassing stimulation of protein kinase C, cytoplasmatic alkalization and generation of nitric oxide. 4. Populational studies demonstrate that there is an inverse association between plasma HDL levels and recurrent venous thromboembolism. In addition, HDL-cholesterol has been identified as an independent predictor of acute platelet thrombus formation. The administration of reconstituted HDL particles in humans attenuates ex vivo platelet activation. 5. The present review summarizes recent advances in understanding HDL-platelet interactions and discusses the potential use of HDL-like particles in the therapy of thrombosis.

Mild Hypercholesterolemia Blunts the Proinflammatory and Prothrombotic Effects of Hypertension on the Cerebral Microcirculation

“…40 High-density lipoprotein also appears to exert antiplatelet effects, including inhibition of agonist induced platelet aggregation, fibrinogen binding, granule secretion, and production of thromboxane A2. 41 In conclusion, the results of this study indicate that mild HCh significantly blunts the recruitment of leukocytes and platelets in the cerebral microvasculature in both low and high Ang II models of HTN. Our findings are also consistent with a role for HDL and ApoA1 as mediators of this antiinflammatory and antithrombogenic effect of a cholesterol-enriched diet.…”

Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice

“…A higher rate of platelet production was also observed for both the S Ϫ L + and S Ϫ L Ϫ mice despite their lower platelet counts, suggesting that these mice must have a higher rate of platelet turnover. Cholesterol enrichment of platelets is known to lead to increased platelet aggregation ( 20,22,75,76 ), which could account for the lower platelet counts in the S Ϫ L + and S Ϫ L Ϫ mice.…”

Regulation of signal transduction by HDL

“…There is also evidence that HDL has direct action on platelets ( 27,28 ). Platelet aggregation stimulated by a variety of means, including by thrombin and ADP, is reduced by HDL, and the lipoprotein also decreases thromboxane A2 and 12-hydroxy-eicosatetraenoic acid release from platelets ( 85,86 ). HDL activates p38MAPK in platelets ( 87 ), and it attenuates intracellular calcium mobilization invoked by LDL cholesterol ( 88 ).…”