Toxicity of oxidized low‐density lipoprotein to cultured fibroblasts is selective for S phase of the cell cycle

Kosugi, Ken’ichirou; Morel, Diane W.; DiCorleto, Paul E.; Chisolm, Guy M.

doi:10.1002/jcp.1041300302

Cited by 98 publications

(32 citation statements)

References 50 publications

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“…Vascular cells have been shown to be more susceptible to oxLDL toxicity during proliferation (8,20,44). In fact, cells become most sensitive to oxLDL injury during the DNA synthesis phase of the cell cycle (26), which is a result of cell cycle entry rather than DNA repair (5). Several mechanisms were offered to explain the proliferative properties of native and modified LDLs in endothelial cells (8,53).…”

Section: Discussionmentioning

confidence: 99%

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

Apostolov¹,

Basnakian²,

Yin³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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Section: Discussionmentioning

confidence: 99%

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

Apostolov¹,

Basnakian²,

Yin³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…The range of the endotoxin level of all preparations was 0.000 to 0.013 pg/g. Electrophoretic mobility (Corning) and thiobarbituric acid reactivity (25,26) were tested in all lipoprotein preparations. Thiobarbituric acid reactivities for LDL were 0.1 to 0.9 nmol of malondialdehyde (as standard)/mg LDL cholesterol, and for oxLDL were 3.9 to 8.1.…”

Section: Methodsmentioning

confidence: 99%

Native and Oxidized Low Density Lipoprotein Induction of Tissue Factor Gene Expression in Smooth Muscle Cells Is Mediated by Both Egr-1 and Sp1

Cui¹,

Penn

Chisolm

1999

Journal of Biological Chemistry

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Tissue factor, in association with factor VIIa, initiates the coagulation cascade. We studied the influences of two pathophysiological stimuli, native (unmodified) and oxidized low density lipoprotein, on tissue factor gene expression in a cell important in vascular remodeling and vascular diseases, the smooth muscle cell. Our results demonstrated that both lipoproteins significantly induced tissue factor gene expression in rat aortic smooth muscle cells; oxidized low density lipoprotein was slightly more potent. Both lipoproteins increased tissue factor mRNA in a concentration-and time-dependent manner. Results from nuclear run-on assays and mRNA stability experiments indicated that increased tissue factor mRNA accumulation in response to the lipoproteins was principally controlled at the transcriptional level. By using lipid extracts of low density lipoprotein or methylation of the intact lipoprotein to block receptor recognition, we showed that this lipoprotein induced tissue factor mRNA via both receptor-independent and receptor-augmented pathways. Transfection studies using a series of deleted tissue factor promoters revealed that a ؊143-to ؉106-base pair region of the rat tissue factor promoter contained regulatory elements required for lipoprotein-mediated induction. Electrophoretic mobility shift assays showed that the binding activities of the transcription factor Egr-1, but not Sp1, were markedly elevated in response to these lipoproteins. Transfection of site-directed mutants of the tissue factor (TF) promoter demonstrated that not only Egr-1 but also Sp1 cis-acting elements in the TF (؊143) promoter construct were necessary for optimal TF gene induction. Our data show for the first time that both low density lipoprotein and oxidized low density lipoprotein induce tissue factor gene expression in smooth muscle cells and that this tissue factor gene expression is mediated by both Egr-1 and Sp1 transcription factors.Tissue factor (TF) 1 expression within the vasculature can activate the coagulation protease cascade and promote thrombotic episodes in a variety of disorders, including cancer, atherosclerosis, and septic shock (reviewed in Refs. 1-3). In atherosclerotic plaques, enhanced TF expression has been detected in association with smooth muscle cells (SMC), macrophages, the lipid-rich necrotic core, and the endothelium overlying the plaque (4 -7). It is important to understand how TF is regulated in SMC, since TF in advancing lesions could exacerbate coagulation after injury, promote SMC proliferation via thrombin generation (8), and reduce atherosclerotic plaque stability.In monocytic cells, endothelial cells, and epithelial cells, TF gene induction by tumor necrosis factor-␣ (TNF-␣), lipopolysaccharide (LPS), phorbol ester (phorbol 12-myristate 13-acetate), and serum is well documented (9 -14). In SMC, serum and various other agonists, including thrombin, platelet-derived growth factor, angiotensin II, and monocyte chemoattractant protein-1, have been shown to induce TF expression in vitro (15,16...

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“…The maximal 14 C release (100%) was obtained from cells lysed with Triton X-100; the minimum release (calculated to be 0%) was from untreated (control) cells. The specific release, expressed as a percentage, was calculated as (cpm released from treated cells Ϫ cpm released from untreated cells) divided by (cpm released by Triton Ϫ cpm released from untreated cells) (35). To examine the effect of vitamin E, cells were treated with vitamin E for 2 h before as well as after adding the agents indicated.…”

Section: Determination Of Dna Synthesis and Protein Synthesis In Smc-mentioning

confidence: 99%

Oxidized Low Density Lipoprotein and Lysophosphatidylcholine Stimulate Cell Cycle Entry in Vascular Smooth Muscle Cells

Chai

Howe

DiCorleto

et al. 1996

Journal of Biological Chemistry

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141

114

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We have previously shown that oxidized low density lipoprotein (LDL) but not native LDL stimulated DNA synthesis in cultured smooth muscle cells (SMC) and that ␣-tocopherol (vitamin E) inhibited this proliferative response (Lafont, A., Chai, Y. C., Cornhill, J. F., Whitlow, P. L., Howe, P. H., and Chisolm, G. M. (1995) J. Clin. Invest. 95, 1018 -1025). The moiety of oxidized LDL that stimulates DNA synthesis and the cellular mechanism for this potentially mitogenic effect are not known. We now report that lipid fractions containing lysophospholipids from oxidized LDL or phospholipase A 2 -treated native LDL stimulated SMC DNA synthesis as did palmitoyl lysophosphatidylcholine (lysoPC). Protein kinase C inhibitors and down-regulation of protein kinase C activity by phorbol ester inhibited oxidized LDLand lysoPC-induced DNA synthesis. A neutralizing monoclonal antibody against fibroblast growth factor-2 significantly inhibited oxidized LDL and lysoPC-induced DNA synthesis in SMC; irrelevant antibodies were ineffective. Vitamin E inhibited the DNA synthesis stimulated by lysoPC, an observation that distinguished this effect from DNA synthesis induced by another detergent, digitonin. These results suggest that oxidized LDL and its lysoPC moiety stimulate SMC to enter the cell cycle via an oxidative mechanism that causes the release of fibroblast growth factor-2 and a subsequent autocrine or paracrine response.

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Toxicity of oxidized low‐density lipoprotein to cultured fibroblasts is selective for S phase of the cell cycle

Cited by 98 publications

References 50 publications

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

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

Native and Oxidized Low Density Lipoprotein Induction of Tissue Factor Gene Expression in Smooth Muscle Cells Is Mediated by Both Egr-1 and Sp1

Oxidized Low Density Lipoprotein and Lysophosphatidylcholine Stimulate Cell Cycle Entry in Vascular Smooth Muscle Cells

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