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

Abstract

Apostolov EO, Basnakian AG, Yin X, Ok E, Shah SV. Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through MAPK pathway. Am J Physiol Heart Circ Physiol 292: H1836 -H1846, 2007. First published December 22, 2006; doi:10.1152/ajpheart.01079.2006.-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 dosedependently increased in the presence of cLDL (6.25-200 g/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 NH 2-terminal kinase (JNK). Inhibition of cLDL-or oxLDL-induced proliferation by aphidicolin (1 g/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 lowdensity lipoprotein; mitogen-activated protein kinase; atherosclerosis CARBAMYLATION is a spontaneous, nonenzymatic reaction of protein modification by cyanate derived from urea, which is normally present in human plasma and is elevated in uremic patients (27). Chronic kidney disease in humans is associated with a several times increased risk of developing cardiovascular diseases because of accelerated atherosclerosis (12,32,47). The mechanism of uremia-induced atherosclerosis is not quite understood. We previously showed (2, 36, 37) that carbamylated low-density lipoprotein (cLDL) induces injury or dysfunction of endothelial cells and is present in human plasma in high quantities. Our recent observation (38) that cLDL induces cell death of human coronary artery endothelial cells (HCAECs) in vitro provided support for this hypothesis.It is commonly accepted that modified LDLs are important for early atherosclerosis initiation and progression (39, 43). Endothelial dysfunction i...

Chronic Uremia Stimulates LDL Carbamylation and Atherosclerosis

“…9,[13][14][15][16] Among those, the role of the intercellular adhesion molecule 1 (ICAM-1) and monocyte adhesion by endothelium were most prominent and, in some conditions, exceeded those induced by oxLDL. 13 To test whether ICAM-1 overexpression and macrophage housing occurred in vivo as a result of uremic atherosclerosis associated with LDL carbamylation, the aortic samples were simultaneously stained for cLDL and for ICAM-1 or CD68, respectively.…”

“…cLDL promotes several biologic processes in vitro that are regarded as pro-atherogenic, including vascular smooth muscle cell proliferation, monocyte adhesion to endothelial cells, 13,14 and endothelial cell cytotoxicity. 9,15,16 However, experimental evidence showing a pro-atherogenic effect of cLDL in vivo is lacking. To obtain this critical evidence, we established two mouse models of elevated plasma urea using (1) a standard model of surgical kidney reduction that mimics CRF in humans 17 and (2) a newly developed, urea consumption (UC) model that elevates plasma urea independently of renal failure.…”

Carbamylated Low-Density Lipoprotein Induces Monocyte Adhesion to Endothelial Cells Through Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1

“…13 Our recent study showed that cLDL induced a variety of damaging stimuli to endothelial and vascular smooth muscle cells, all of which are attributed to atherosclerosis. 10,14 These include incorporation by endothelial cells, cytotoxicity toward endothelial cells, and the induction of vascular smooth muscle cell proliferation.…”

Low-Density Lipoproteins Induce Heat Shock Protein 27 Dephosphorylation, Oligomerization, and Subcellular Relocalization in Human Vascular Smooth Muscle Cells

“…20 It has been reported that modified LDL (oxidated, glycated) can induce p38 MAPK transient activation in different cell types. [35][36][37][38] However, the significant decrease in pHSP27, below control levels, after 24 hours of treatment with LDL is neither related to p38 MAPK activity nor to MAPKAPK2. LDL-related dephosphorylation of HSP27 is not due to the switch-off of MAPK but to a counterregulation by PPA2, 39 because inhibition of PPA2 by either OA or fostriecin blocked the effect of LDL on pHSP27.…”