Diabetic LDL Triggers Apoptosis in Vascular Endothelial Cells

Abstract

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.