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The clot thickens-oxidized lipids and thrombosis
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Nature Medicine 13, 1015 - 1016 (2007)
doi:10.1038/nm0907-1015
Shaun P Jackson1 & Anna C Calkin2
1. Shaun P. Jackson is at the Australian Centre for Blood Diseases, Monash University, Melbourne, Australia. e-mail: shaun.jackson@med.monash.edu.au
2. Anna C. Calkin is at the Baker Heart Research Institute, Alfred Medical Research & Education Precinct, Melbourne, Australia. e-mail: anna.calkin@baker.edu.au
Abstract
Oxidized products of low-density lipoproteins (LDLs) activate platelets through CD36, demonstrating a link between deregulated lipoprotein levels, oxidative stress and thrombosis (pages 1086-1095): "Dyslipidemia is associated with both oxidative stress and the generation of biologically active oxidized lipids....ultiple studies have shown that dyslipidemia, a major risk factor for atherosclerosis, is associated with enhanced platelet reactivity and increased thrombogenic potential.....Using two different mouse models of hyperlipidemia and several assays for in vivo thrombosis, we confirmed that hyperlipidemia induces a pronounced prothrombotic state; these findings are consistent with prior observations in Apoe-/- mic"
"High-fat diets, sedentary lifestyles and genetic predispositions can all conspire to dysregulate lipoprotein levels. Dyslipidemias are associated with oxidative stress and the generation of atherogenic oxidized lipids, notably oxidized LDL (oxLDL). oxLDL can induce endothelial dysfunction, monocyte recruitment and foam-cell formation, and can also promote inflammatory changes in the vessel wall-all important factors in atherogenesis.....how dyslipidemia leads to arterial thrombosis......direct lipoprotein particle signaling through receptors on the platelets. Mechanisms such as these could activate platelets, causing them to aggregate and form a thrombus."
In their study, Podrez et al. confirmed previous reports that mice with severe defects in lipoprotein metabolism form clots more quickly in response to injury in vivo than healthy control mice4, 5. Mice deficient in either apolipoprotein E (apoE) or the LDL receptor (LDLR) had this increased thrombotic response, but Podrez et al. found that clot formation was most accelerated when these mice were fed a high-fat diet compared to when these mice were fed a normal diet.....Together, these data indicate that both a baseline dyslipidemia and a high-fat diet are required for the prothrombotic phenotype.
he results reported in this study are striking and suggest that diet-induced modifications of LDL during dyslipidemia cause the generation of the newly recognized prothrombotic molecules, oxPCCD36. These findings raise interesting possibilities for therapeutic regulation of platelet reactivity in individuals with dyslipidemia. In principle, platelet activation by oxPCCD36 could be dampened by reducing concentrations of oxPCCD36 or by blocking its interaction with CD36.
Antagonizing CD36 receptor function, however, may not be problem free. Although somewhat controversial, there have been reports that CD36-deficient individuals show features of the metabolic syndrome, including dyslipidemia and mildly elevated blood pressure10. Therapeutic approaches that selectively block the interactions between oxPCCD36 and CD36 might be the best option for minimizing metabolic disturbances while manipulating platelet reactivity.
One of the major obstacles to increased longevity is atherosclerosis, an inflammatory disorder that leads to fibrous, fatty lesions in the arterial wall. Advanced atherosclerotic lesions (plaques) are prone to rupture, exposing thrombogenic elements that promote excessive platelet and fibrin accumulation, leading to the formation of arterial thrombi (clots). Although atherosclerosis is bad news, superimposed thrombosis is deadly. Clots precipitate acute coronary syndromes and ischemic stroke, which are the leading causes of death and disability in industrialized societies. Many individuals with atherosclerosis have hyperreactive platelets that may exacerbate their thrombotic risk. This risk is further increased when plasma lipid metabolism is deregulated in a common condition known as dyslipidemia.
Given the magnitude of the clinical problem, new insights into the mechanisms by which atherogenic lipids promote thrombosis are welcome. In this issue of Nature Medicine, Podrez et al. show that oxidized choline glycerophospholipids (oxPCCD36) cause platelet activation through CD36, and that the levels of oxPCCD36 rise when deregulated lipid levels are worsened by a high-fat diet1. This work provides fundamental new insights into the relationship between dyslipidemia, oxidative stress and thrombosis.
Dyslipidemias are one of the dominant risk factors associated with atherothrombotic disorders2. Individuals with dyslipidemia typically have increased plasma concentrations of triglycerides and low-density lipoprotein (LDL) cholesterol (so called 'bad' cholesterol) and decreased concentrations of high-density lipoprotein (HDL) cholesterol ('good' cholesterol). High-fat diets, sedentary lifestyles and genetic predispositions can all conspire to dysregulate lipoprotein levels. Dyslipidemias are associated with oxidative stress and the generation of atherogenic oxidized lipids, notably oxidized LDL (oxLDL). oxLDL can induce endothelial dysfunction, monocyte recruitment and foam-cell formation, and can also promote inflammatory changes in the vessel wall-all important factors in atherogenesis.
For many years it has been known that oxLDL enhances platelet activation3, but how dyslipidemia leads to arterial thrombosis has been less clearly defined. Some possibilities include changes in platelet membrane cholesterol and oxidative injury to membrane lipids and surface glycoproteins, as well as direct lipoprotein particle signaling through receptors on the platelets. Mechanisms such as these could activate platelets, causing them to aggregate and form a thrombus. Podrez et al. shed new light on how deregulated lipid levels affect this process by identifying oxidatively modified LDL products that enhance platelet activation and thrombus formation1.
In their study, Podrez et al. confirmed previous reports that mice with severe defects in lipoprotein metabolism form clots more quickly in response to injury in vivo than healthy control mice4, 5. Mice deficient in either apolipoprotein E (apoE) or the LDL receptor (LDLR) had this increased thrombotic response, but Podrez et al. found that clot formation was most accelerated when these mice were fed a high-fat diet compared to when these mice were fed a normal diet. This observation was somewhat surprising because apoE-deficient and LDLR-deficient mice have defects in lipoprotein metabolism irrespective of the fat content in their diet5, and thus indicated that high lipoprotein concentrations are not the only cause of the heightened thrombotic response. What's more, Podrez et al. showed that wild-type mice fed the high-fat diet did not have increased clot formation in response to injury1. Together, these data indicate that both a baseline dyslipidemia and a high-fat diet are required for the prothrombotic phenotype. These observations stimulated Podrez and colleagues to search for prothrombotic molecules that are induced by a high-fat diet.
Podrez et al. had recently characterized a new class of oxidized choline glycerophospholipids, termed oxPCCD36, that promote foam-cell formation, a key process of atherogenesis6. Notably, these lipids circulate at much higher concentrations (up to 30-fold) in apoE-deficient and LDLR-deficient mice that are fed a high-fat diet1. These molecules are generated by the oxidation of LDL by a number of pathways, including the myeloperoxidase-hydrogen peroxide-nitrite (MPO-H2O2-NO2-) system (Fig. 1). This pathway may be particularly relevant, as MPO is a strong and independent marker of coronary artery disease7, and levels of both MPO and oxPCCD36 are increased in atherosclerotic plaques6.
Podrez et al. showed that pathophysiological concentrations of oxPCCD36 induce platelet activation as effectively as a soluble agonist, a striking observation given that platelets are continually exposed to such lipids in the circulation1. These results suggest that oxPCCD36 generation is a diet-related phenomenon that can enhance platelet reactivity and induce a prothrombotic phenotype.
oxPCCD36 are high-affinity ligands for the scavenger receptor CD36, which is expressed on platelets8. CD36 can bind several platelet-adhesive ligands, yet its role in platelet function has remained elusive. Podrez et al. convincingly demonstrate that the increased platelet reactivity and the prothrombotic phenotype of apoE-deficient and LDLR-deficient mice can be directly attributed to the interaction of oxPCCD36 with CD36 on platelets1. What's more, oxPCCD36 did not increase platelet reactivity in CD36-deficient mice. Podrez et al. also report similar findings in humans: plasma oxPCCD36 concentration correlated with platelet reactivity, but this correlation was not seen in CD36-deficient individuals, suggesting that oxPCCD36 influences platelet reactivity through CD36 in human plasma, as well.
Podrez et al. also investigated the relationship between plasma oxPCCD36 and cholesterol. Although oxPCCD36 are present on oxLDL, no association between plasma oxPCCD36 and LDL cholesterol was apparent1. By contrast, there was a strong inverse correlation between oxPCCD36 and HDL cholesterol. HDL has antioxidative properties that may affect the generation of oxidized phospholipids such as oxPCCD36. In addition, HDL has important, as yet ill-defined platelet-inhibitory properties. The high levels of HDL may partly explain the decreased platelet responsiveness in individuals with low levels of oxPCCD36.
The results reported in this study are striking and suggest that diet-induced modifications of LDL during dyslipidemia cause the generation of the newly recognized prothrombotic molecules, oxPCCD36. These findings raise interesting possibilities for therapeutic regulation of platelet reactivity in individuals with dyslipidemia. In principle, platelet activation by oxPCCD36 could be dampened by reducing concentrations of oxPCCD36 or by blocking its interaction with CD36. CD36 deficiency in humans and mice seems to be well tolerated and does not cause any overt platelet defects, suggesting that blocking platelet CD36 is unlikely to produce bleeding side effects, a problem that plagues all commonly used antithrombotic treatments. Further, the findings by Podrez et al. may explain some of the antithrombotic benefits of statins, which have been shown to decrease CD36 expression on platelets9.
Antagonizing CD36 receptor function, however, may not be problem free. Although somewhat controversial, there have been reports that CD36-deficient individuals show features of the metabolic syndrome, including dyslipidemia and mildly elevated blood pressure10. Therapeutic approaches that selectively block the interactions between oxPCCD36 and CD36 might be the best option for minimizing metabolic disturbances while manipulating platelet reactivity.
At the very least, elevated levels of oxPCCD36 may become an important marker of heightened platelet reactivity. Information about oxPCCD36 levels may influence decisions regarding the use of more aggressive antithrombotic and antiatherogenic therapies in individuals at increased cardiovascular risk. Now that the lid has been lifted on this potentially important relationship between dyslipidemia, oxidative stress and platelet function, be prepared for the deluge of clinical studies aimed at validating the significance of these provocative findings.
References
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