Atherogenic lipoproteins, oxidative stress, and cell death.
BACKGROUND
Glomerulosclerosis and atherosclerosis are chronic inflammatory processes that may be influenced by oxidized lipoproteins, oxidized low-density lipoproteins (oxLDL), and oxidized lipoprotein(a) [oxLp(a)]. We hypothesize that these lipoproteins contribute to the development of glomerulosclerosis and atherosclerosis through the induction of oxidative stress, which influences cell viability. We therefore determined the impact of oxLDL and oxLp(a) on O2- formation and on necrotic and apoptotic cell death in vascular and glomerular cells.


METHODS
The impact of human LDL and Lp(a) (oxidized with CuSO4) on O2- formation (detected with a chemiluminescence method), apoptosis, and necrosis (determined with the annexin assay) was studied in cultured human umbilical vein endothelial cells (ECs) and in cultured human mesangial cells (MCs).


RESULTS
O2- formation was increased by 10 micrograms/ml oxLDL (by factor 2.5 in ECs) and by 5 micrograms/ml oxLp(a) (by factor 3.5 in ECs). OxLDL and oxLp(a) both significantly and dose-dependently increased the rate of apoptotic cell death in ECs and in MCs, with oxLp(a) being the more potent stimulus that also caused necrosis. The induction of apoptosis by oxLDL and oxLp(a) in ECs and MCs was enhanced by inhibition of the endogenous superoxide dismutase (SOD) with diethyl-dithio-carbamate and was blunted by the antioxidants N-acetylcysteine, vitamin C + E, SOD, and catalase, suggesting that oxidative stress was the stimulus for apoptosis.


CONCLUSIONS
These data suggest that oxLDL and oxLp(a) contribute to inflammation by stimulating O2- formation, leading to apoptotic cell death in the vascular wall and in the glomerulus. The oxidized lipoproteins may thereby influence the pathogenesis of atherosclerosis and glomerulosclerosis.
Department of Medicine, University Hospital of Würzburg, Germany. j-c.galle@mail.uni-wuerzburg.de
J
J
Galle
K
K
Heermeier
C
C
Wanner
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001161:Arteriosclerosis / Q000209:etiology*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D017270:Lipoprotein(a) / Q000378:metabolism / Q000494:pharmacology; D008074:Lipoproteins / Q000378:metabolism / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000502:physiology
D017270:Lipoprotein(a); D008074:Lipoproteins; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein