Inflammation, atherosclerosis, and arterial thrombosis: Role of the scavenger receptor CD36
ABSTRACT
The CD36 scavenger receptor recognizes oxidized low-density lipoprotein (LDL) and cell-derived microparticles. It is expressed on macrophages and platelets and is a mediator of both atherogenesis and thrombosis. Macrophages from CD36-null mice have a defect in foam cell formation in response to exposure to oxidized LDL, and CD36-null mice fed an atherogenic Western diet have significantly less atherosclerosis than their wild-type counterparts. On platelets, CD36 recognition of oxidized LDL contributes to their activation and provides a mechanistic link between hyperlipidemia, oxidant stress, and the prothrombotic state. Cell-derived microparticles are also major ligands for CD36 and contribute to thrombus formation in a CD36-dependent manner even in the absence of hyperlipidemia. CD36 deficiency in mice is associated with inhibition of thrombus formation and with a reduction in microparticle accumulation in thrombi. Targeting CD36 is a promising avenue for the treatment of atheroinflammatory disorders.
Platelet activation in the setting of hyperlipidemia
In addition to the formation and progression of plaque, CD36 may be involved in the terminal phases of atherosclerosis (ie, the thrombosis that occurs on a plaque) as a result of abundant CD36 expression on platelets. CD36, in fact, was discovered as a platelet protein and named platelet glycoprotein IV, although for many years the function of CD36 on platelets was not known.
Recent studies by Podrez and colleagues, along with our group, revealed that oxLDL binds to the surface of platelets in a concentration-dependent manner, whereas normal LDL does not. The binding of oxLDL to platelets can be blocked almost completely by inhibiting CD36 with an antibody; binding did not occur with platelets obtained from CD36-deficient mice or people.7 Importantly, exposure to oxLDL caused platelets to be activated via a highly specific cell-signaling pathway; low concentrations of oxLDL, such as those found in plasma of individuals with even modest hyperlipidemia, made platelets more sensitive to low doses of “classic” platelet agonists such as collagen and adenosine diphosphate (ADP).8 These studies suggest that platelet CD36 could serve as a mechanistic link between inflammation, oxidant stress, and hyperlipidemia to create a prothrombotic state.
It has been known for some time through the work of Eitzman and others that apoE-null mice fed a Western diet are “hypercoagulable”; ie, they have shortened thrombosis times.9 This observation led us to investigate the role of CD36 in the hyperlipidemia-associated prothrombotic state. In one experiment, tail-vein bleeding times were measured in apoE-null and apoE/CD36-double-null mice fed a high-fat diet. Whereas the apoE-null animals had markedly shortened bleeding times (~ 2 minutes), the double CD36/apoE-null animals were normal (~ 6–8 minutes).
To examine a model more reflective of pathologic thrombus formation (eg, heart attack, stroke), we induced carotid artery injury in mice by topical application of ferric chloride. This method induces oxidant injury to the endothelium and causes platelet-dependent carotid occlusion. With this model, thrombosis can be monitored in “real time” with a Doppler flow probe and video microscope. As with tail-vein bleeding time, we found that time to carotid occlusion was much shorter in apoE-null mice fed a high-fat diet than in mice fed a normal chow diet or in wild-type mice; further, this prothrombotic state was rescued by genetic ablation of CD36 expression.7
Possible role in thrombus formation
More recent experiments from our lab have shown that CD36-null mice fed a normal chow diet have a subtle defect in thrombus formation when arteries or veins are subjected to relatively mild injury.10 This finding implies a potential role for CD36 in “normal” platelet function and perhaps the existence of an endogenous ligand for CD36 that is unrelated to hyperlipidemia. Since we know that CD36-null mice and CD36-deficient people do not have a bleeding disorder and have normal bleeding times, it is possible that pharmacologic targeting of CD36 may provide a means to inhibit thrombosis without having a major impact on hemostasis.
The possibility that mice or humans can be protected from developing thrombi by blocking CD36 function is supported by initial data obtained from the carotid artery injury model in mice. In the laboratory, an antithrombotic state can be created by blocking the specific CD36-signaling pathway described below. Thrombocytopenic wild-type mice transfused with platelets from wild-type mice exhibit a dramatic increase in thrombosis time when the donor platelets are pretreated with a CD36-signaling inhibitor.8 This protective effect vanishes when the same experiment is performed in CD36-null mice.
