CD36: a multi-modal target for acute stroke therapy

Abstract

A role for CD36 in the pathogenesis of atherosclerosis, inflammation and lipid metabolism has been well-documented. However, little is known about the role of CD36 in cerebral ischemia. The intent of this review is to develop the concept that CD36, whose functions have been implicated in other pathological events, is a prototypic inflammatory receptor that contributes to the pathogenesis of cerebral ischemia. The importance of CD36 as a treatment target is indicated by the fact that many treatment strategies that are effective in experimental models of stroke exhibit little or no efficacy in clinical trials. The failure of clinical trials may be due to the use of animal models of stroke that do not reflect traditional risk factors for stroke in humans. The discussion will be focused on two risk factors, hyperlipidemia and diabetes, that modulate CD36 responses. Blocking the expression and function of CD36 by pharmacological or genetic means will provide insight not only toward identifying CD36 as a novel molecular target but also for developing effective therapeutic strategies to treat stroke victims. More importantly, coupling clinically relevant conditions with CD36-mediated ischemic injury may provide an appropriate animal model paradigm and develop a scientific understanding that could lead to clinical translational studies involving human subjects.

Figure 1. A proposed multimodal strategy for stroke using CD36 as a target

A, The binding of thrombospondins (TSPs) elicits an anti-angiogenic signaling cascade that causes apoptosis of endothelial cells. By recognizing pathogen-associated molecular patterns of dying cells, CD36 is involved in innate immunity. In response to fibrillar Aβ (fAβ), CD36 mediates an innate host response. Foam cell formation by uptake of oxLDLs contributes to atherosclerotic lesion development. CD36 translocates long chain fatty acids (LCFA) across the plasma and mitochondrial membrane and involved in lipid metabolism. Ligands/receptor interactions markedly induce CD36 gene and protein expression in a feed forward manner and results in pathological consequences. B, Blocking CD36 by genetic or pharmacological means results in interruption of the feed forward loop, down-regulates CD36 pathways, and leads to global protection against pathological conditions such as stroke. L, ligands; Inh, Inhibitors

Figure 2. Hyperlipidemia-promoted foam cell formation

Oil-red O staining in the ipsilateral side of normolipidemic (NL) and hyperlipidemic (HL) brain 3 days following ischemia. No foam cells were observed in the normolipidemic brain. On the contrary, there are numerous oil-red O stained foam cells in the penumbra from the hyperlipidmic brain. The lower panels show the higher magnification of the boxed areas. Scale bar, 500 μm

Figure 3. CD36 exacerbates ischemic injury in predisposing clinical conditions

Upon ischemia-reperfusion in normal condition, CD36 ligands such as free fatty acids (FFAs) and oxLDLs are generated. Interactions between CD36 and the liberated ligands generate reactive oxygen/nitrogen species and pro-inflammatory mediators, and contribute to ischemia-induced injury. Excessive ligands are generated in hyperlipidemic (FFAs, oxLDLs) and diabetic conditions (advanced glycated endproducts (AGEs), glycated-oxLDL(Glyc-oxLDL)). Enhanced receptor/ligand interactions further increase CD36 expression and the feed forward loop exacerbates ischemia-induced inflammation and injury. FFA, free fatty acid; AGE, advanced glycated end products; Glyc-oxLDL, glycated-oxidized LDL