Structural Basis for the Recognition of Oxidized Phospholipids in Oxidized Low Density Lipoproteins by Class B Scavenger Receptors CD36 and SR-BI

Abstract

Specific oxidized phospholipids (oxPC CD36 ) accumulate in vivo at sites of oxidative stress and serve as high affinity ligands for scavenger receptors class B (CD36 and SR-BI). Recognition of oxPC CD36 by scavenger receptors plays a role in several pathophysiological processes. The structural basis for the recognition of oxPC CD36 by CD36 and SR-BI is poorly understood. A characteristic feature of oxPC CD36 is an sn-2 acyl group that incorporates a terminal ␥-hydroxy (or oxo)-␣,␤-unsaturated carbonyl. In the present study, a series of model oxidized phospholipids were designed, synthesized, and tested for their ability to serve as ligands for CD36 and SR-BI. We demonstrated that intact the sn-1 hydrophobic chain, the sn-3 hydrophilic phosphocholine or phosphatidic acid group, and the polar sn-2 tail are absolutely essential for high affinity binding. We further found that a terminal negatively charged carboxylate at the sn-2 position suffices to generate high binding affinity to class B scavenger receptors. In addition, factors such as polarity, rigidity, optimal chain length of sn-2, and sn-3 positions and negative charge at the sn-3 position of phospholipids further modulate the binding affinity. We conclude that all three positions of oxidized phospholipids are essential for the effective recognition by scavenger receptors class B. Furthermore, the structure of residues in these positions controls the affinity of the binding. The present studies suggest that, in addition to oxPC CD36 , other oxidized phospholipids observed in vivo may represent novel ligands for scavenger receptors class B. Specific oxidized phospholipids (oxPC CD36 )3 accumulate at sites of oxidative stress in vivo such as within atherosclerotic lesions and plasma in dyslipidemia (1, 2). They serve as high affinity ligands for scavenger receptors class B: CD36 and SR-BI (3, 4). Recognition of oxPC CD36 on the surface of cell membranes and lipoprotein particles by scavenger receptors class B plays an important role in several pathophysiological processes, including atherosclerosis and thrombosis. oxPC CD36 phospholipids mediate uptake of oxidized low density lipoprotein (oxLDL) by macrophages via CD36 and promote a pro-thrombotic state via platelet scavenger receptor CD36 (1, 2). oxPC CD36 phospholipids also prevent binding of high density lipoprotein by SR-BI because of the close proximity of the binding sites for these two ligands on SR-BI. Furthermore, oxPC CD36 interfere with SR-BI-mediated selective uptake of cholesteryl esters in hepatocytes (4). These data demonstrate that oxidative stress and accumulation of specific oxidized phospholipids may have a detrimental effect due to specific interaction with scavenger receptors class B. However, the exact molecular mechanism of the recognition of oxPC CD36 by scavenger receptors class B is poorly understood.Initial studies have demonstrated that the sn-2 acyl group of oxPC CD36 that incorporates a terminal ␥-hydroxy (or oxo)-␣,␤-unsaturated carbonyl is essential for high affinity binding to...

Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids

“…In contrast, our studies with POVPC-exposed macrophages show a prominent increase in several proinfl ammatory cytokines, such as TNF-␣ , IL-6, IL-8, and IL-1 ␤ , that play a central role in infl ammation. Thus, there may by the PAF-receptor, scavenger receptor B-I, or CD36 ( 39,40 ). Thus, changes in the structure of the sn -2 group during metabolism could drastically affect the biological activity of these phospholipids.…”

<b>Identification of the odor-active volatile compound (</b><i><b>Z</b></i><b>,</b><i><b>Z</b></i><b>)-4,7-tridecadienal as a potential ligand for the transmembrane receptor </b><b>CD36 </b>

“…All the products were purified by silica gel chromatography and were subjected to 1 H-and 13 C-nuclear magnetic resonance spectrometry and gas chromatograph-mass spectrometry for quality assessment. On the basis of gas chromatography, the puriimportant for interactions with the binding site (5). Recently, we and others have demonstrated that CD36 is produced by distinct types of olfactory sensory neurons and is abundantly present on the surface of the olfactory epithelium (i.e., on the ciliary layer) in mice (14,18,31).…”

Synthetic Amphipathic Helical Peptides Targeting CD36 Attenuate Lipopolysaccharide-Induced Inflammation and Acute Lung Injury

“…Furthermore, recent data suggest that CD36 is one of the most important receptors associated with bacterial uptake, bacterial endotoxic cellular cytotoxicity (28), and acute and chronic kidney injury (28,(55)(56)(57). These recent data suggest that the vicious cycles of pathogen associated molecular pattern-induced inflammation and DAMP-induced tissue damage may well be mediated through CD36 (58,59). At the same time, independently of the specific mechanisms affecting lung inflammation, SAHPs are important tools that decrease pulmonary damage induced by proinflammatory compounds (51,60).…”