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This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/H1836    most recent 01079.2006v2 01079.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Apostolov, E. O. Articles by Shah, S. V. Search for Related Content PubMed PubMed Citation Articles by Apostolov, E. O. Articles by Shah, S. V.

Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through MAPK pathway

¹Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences and ²Central Arkansas Veterans Healthcare System, Little Rock, Arkansas

Submitted 2 October 2006 ; accepted in final form 1 December 2006

The ability of modified low-density lipoptoteins (LDLs) to induce both proliferation and death of endothelial cells is considered to be a mechanism of early atherosclerosis development. We previously showed that carbamylated LDL (cLDL) induces human coronary artery endothelial cell (HCAEC) death in vitro. This effect is similar to the atherogenic action of oxidized LDL (oxLDL) that induces the proliferation and death of endothelial cells. The present study was designed to analyze a potential proliferative effect of cLDL and whether proliferation caused by modified LDLs is related to cell death. Cultured HCAECs were exposed to different concentrations of modified LDL or native LDL for varying periods of time. Cell proliferation measured by bromodeoxyuridine incorporation and S-phase analysis was dose-dependently increased in the presence of cLDL (6.25–200 µg/ml). The proliferation induced by cLDL or oxLDL was associated with cell death and increased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH₂-terminal kinase (JNK). Inhibition of cLDL- or oxLDL-induced proliferation by aphidicolin (1 µg/ml) was protective against both short-term cell death measured by lactate dehydrogenase release into the medium and long-term cell viability visualized by cell multiplication. Inhibition of ERK phosphorylation led to a significant decrease of DNA synthesis and cell rescue from injury by modified LDLs, while inhibition of JNK phosphorylation had an only partial rescue effect without involvement in cell proliferation. These data are the first evidence that endothelial cell death induced by cLDL or oxLDL is mediated by cell proliferation through the mitogen-activated protein kinase pathway.

carbamylation; carbamylated low-density lipoprotein; oxidized low-density lipoprotein; mitogen-activated protein kinase; atherosclerosis