Diabetic LDL triggers apoptosis in vascular endothelial cells.
This study compares the effects of LDL glycated either in vitro (LDL(iv)) or in vivo in diabetic patients (LDL(D)) on apoptosis, proliferation, and associated protein expression in cultured human umbilical vein endothelial cells. At 100 mg/l, both LDL species considerably increase apoptosis (LDL(iv) 63%, LDL(D) 40%; P < 0.05) compared with intraindividual nonglycated LDL subfractions. Considering its lower degree of glycation (LDL(D) 5-10%, LDL(iv) 42%), LDL(D)'s relative proapoptotic activity is 2.7-fold greater than that of LDL(iv). Glycated LDL-induced apoptosis is associated with increased expression of apoptosis promotors (LDL(iv): bak 88%, CPP-32 49%; LDL(D): bak 18%, CPP-32 11%; P < 0.05) and is attenuated by caspase inhibitors. Glycated LDL's antiproliferative activity (LDL(iv) -34%, LDL(D) -9%; P < 0.01) relates to reduction (P < 0.05) of cyclin D3 (LDL(iv) -27%, LDL(D) -24%) and of hypo- (LDL(iv) -22%, LDL(D) -19%) and hyperphosphorylated (LDL(iv) -53%, LDL(D) -22%) retinoblastoma protein and is paralleled by reduced expression of endothelial nitric oxide synthase (LDL(iv) -30%, LDL(D) -23%). In response to lipoprotein lipase, LDL(D) more markedly triggers endothelial apoptosis (27.1-fold) compared with LDL(iv), suggesting that LDL(D) owns a higher potential for endothelial cell damage than LDL(iv). The observed behavior of LDL(D) versus LDL(iv) could be of clinical importance and well relate to differences in structure and cellular uptake of LDL(D) compared with LDL(iv).
Artwohl
Michaela
M
Department of Internal Medicine III, Division of Clinical Endocrinology and Metabolism, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Graier
Wolfgang F
WF
Roden
Michael
M
Bischof
Martin
M
Freudenthaler
Angelika
A
Waldhäusl
Werner
W
Baumgartner-Parzer
Sabina M
SM
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000494:pharmacology; D017127:Glycation End Products, Advanced; D006031:Glycosylation; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D014471:Umbilical Veins; D000093844:Glycated Proteins
D004247:DNA; D005947:Glucose; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C099252:oxidized low density lipoprotein