HDL and the Inflammatory Response Induced by LDL-Derived Oxidized Phospholipids

Abstract

Abstract-Oxidation of low density lipoprotein (LDL) phospholipids containing arachidonic acid at the sn-2 position occurs when a critical concentration of "seeding molecules" derived from the lipoxygenase pathway is reached in LDL. When this critical concentration is reached, the nonenzymatic oxidation of LDL phospholipids produces a series of biologically active, oxidized phospholipids that mediate the cellular events seen in the developing fatty streak. Normal high density lipoprotein (HDL) contains at least 4 enzymes as well as apolipoproteins that can prevent the formation of the LDL-derived oxidized phospholipids or inactivate them after they are formed. In the sense that normal HDL can prevent the formation of or inactivate these inflammatory LDL-derived oxidized phospholipids, normal HDL is anti-inflammatory. HDL from mice that are genetically predisposed to diet-induced atherosclerosis became proinflammatory when the mice are fed an atherogenic diet, injected with LDL-derived oxidized phospholipids, or infected with influenza A virus. Mice that were genetically engineered to be hyperlipidemic on a chow diet and patients with coronary atherosclerosis, despite normal lipid levels, also had proinflammatory HDL. It is proposed that LDL-derived oxidized phospholipids and HDL may be part of a system of nonspecific innate immunity and that the detection of proinflammatory HDL may be a useful marker of susceptibility to atherosclerosis. (Arterioscler Thromb Vasc Biol. 2001;21:481-488.)Key Words: HDL Ⅲ LDL Ⅲ atherosclerosis Ⅲ oxidized phospholipids T he events involved in fatty streak formation resemble those elicited by mycobacteria. 1 Over the past decade, there has been increasing evidence that this inflammatory response may, in part, be elicited by the oxidation of phospholipids contained in LDL. 2,3 Several oxidized phospholipids that are able to induce the genes and proteins necessary for the cellular response seen in the fatty streak have been identified in mildly oxidized LDL and in lesions of animal models of atherosclerosis. 4 -9 Two of these oxidized phospholipids, 1-palmitoyl-2(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC) and 1-palmitoyl-2-glutaroyl-snglycero-3-phosphorylcholine (PGPC), both induced monocytes to bind to endothelial cells. 10 However, PGPC but not POVPC also induced neutrophils to bind to endothelial cells. 10 Indeed, POVPC strongly inhibited lipopolysaccharide-mediated induction of neutrophil binding and expression of E-selectin protein and mRNA. 10 This inhibition by POVPC was mediated by a protein kinase A-dependent pathway that resulted in downregulation of nuclear factor-B-dependent transcription. 10 PGPC, on the other hand, induced both E-selectin and vascular cell adhesion molecule-1 (VCAM-1) expression on endothelial cells. 10 On the basis of studies in Xenopus laevis oocytes, Leitinger et al 10 concluded that POVPC and PGPC bound to different receptors. Furthermore, they demonstrated that at concentrations equal to those present in mildly oxidized LDL, POVPC prevente...

Enzymatically Active Paraoxonase-1 Is Located at the External Membrane of Producing Cells and Released by a High Affinity, Saturable, Desorption Mechanism

“…In vitro studies have demonstrated the capacity of PON1 to prevent LDL (and HDL) oxidation by a variety of pro-oxidant factors, including cellinduced LDL oxidation (1,2). Complementary studies have shown that the anti-oxidant activity of PON1 prevents LDL from acquiring a number of pathological characteristics associated with the atherosclerotic process, notably monocyte mobilization and gene activation (3). The PON1 knockout mouse model confirmed that absence of serum PON1 activity increases the level of lipoprotein oxidation, renders LDL more susceptible to oxidation, decreases the anti-oxidant capacity of HDL and leads to more extensive atheroma formation (4,5).…”

“…Incidentally, the SR-B1 receptor was detected immunologically in the CHO-hPON1 line. 3 The particular feature of SR-B1 function is to allow bi-directional transfer of hydrophobic molecules between lipoprotein and cell, without internalization of the lipoprotein particle. We hypothesize that PON1 may exploit this mechanism to allow secretion and correct insertion into the HDL complex.…”

High‐Density Lipoprotein Cholesterol Concentration and Acute Kidney Injury After Cardiac Surgery

“…High‐density lipoproteins (HDLs) have systemic anti‐inflammatory and antioxidant properties and limit endothelial dysfunction and damage by attenuating endothelial cell activation and adhesion molecule expression, by activating endothelial nitric oxide synthase, and by promoting endothelial repair 10, 13, 14, 15, 16, 17, 18, 19, 20. In critically ill patients with pneumonia or sepsis, low HDL cholesterol concentrations are associated with multiorgan dysfunction and short‐ and long‐term death 21, 22.…”

Import and fate of fluorescent analogs of oxidized phospholipids in vascular smooth muscle cells

“…On the basis of studies in Xenopus laevis oocytes, Leitinger and colleagues (64) concluded that POVPC and PGPC elicit their cellular responses through binding to different receptors. This adds to earlier indications that the effects of oxidized phospholipids are receptor-mediated.…”