Oxidized phospholipids, isolevuglandins, and atherosclerosis.
Autoxidation of polyunsaturated phosphatidylcholines (PCs) generates isolevuglandins (isoLGs) through rearrangements of isoprostanoid endoperoxides. Within seconds, isoLGs are sequestered by covalent adduction with proteins. Murine plasma isoLG-protein levels increased at least 2.5-fold in response to inflammation. IsoLG-protein adducts accumulate in vivo providing a convenient dosimeter of oxidative stress. Elevated blood isoLG-protein levels present in atherosclerosis (AS) patients point to an independent defect that is not associated with total cholesterol levels, which results in an abnormally high level of oxidative injury in AS. Protein adduction and cross-linking caused by isoLGs can obstruct protein function. For example, it interferes with proteosomal degradation of proteins and, consequently, may result in apoptotic death of smooth muscle cells and destabilization of atherosclerotic plaques. Phospholipid autoxidation also generates biologically active oxidatively truncated PCs through fragmentation of dihydroperoxydienes that can be promoted by alpha-tocopherol. The oxidatively truncated PCs in oxidized low-density lipoprotein (oxLDL) contribute to the etiology of AS by inhibiting enzymatic activities required for normal processing of oxLDL by macrophages. They promote interactions of monocytes with endothelial cells that may foster migration of monocytes into the subendothelial space. They are also ligands for unregulated receptor-mediated uptake of oxLDL by monocyte macrophages leading to foam cell formation.
Zhang
Wujuan
W
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106-7078, USA.
Salomon
Robert G
RG
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000097:blood*; D001798:Blood Proteins / Q000378:metabolism; D003432:Cross-Linking Reagents; D005231:Fatty Acids, Unsaturated / Q000097:blood*; D005609:Free Radicals / Q000494:pharmacology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000737:chemistry; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010713:Phosphatidylcholines / Q000097:blood; D010743:Phospholipids / Q000097:blood*; D015539:Platelet Activation / Q000502:physiology; D011453:Prostaglandins / Q000737:chemistry; D011485:Protein Binding; D012307:Risk Factors
D000447:Aldehydes; D001798:Blood Proteins; D003432:Cross-Linking Reagents; D005231:Fatty Acids, Unsaturated; D005609:Free Radicals; D008077:Lipoproteins, LDL; D010713:Phosphatidylcholines; D010743:Phospholipids; D011453:Prostaglandins; C099252:oxidized low density lipoprotein