Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidized LDL (oxLDL) may contribute to the accumulation of apoptotic cells in atherosclerotic plaques. Although it is well established in monophasic chemical systems that the highly unsaturated EPA and DHA will oxidize more readily than FA that contain fewer double bonds, our previous studies showed that enrichment of LDL, which has discrete polar and nonpolar phases, with these FA did not increase oxidation. The objective of this study was to compare the extent of apoptosis induced by EPA/DHA-rich oxLDL to that induced by EPA/DHA-non-rich oxLDL in U937 cells. LDL was obtained from one healthy subject three times before and after supplementation for 5 wk with 15 g/d of fish oil (FO), an amount easily obtainable from a diet that contains fatty fish. After supplementation, an EPA/DHA-rich LDL was obtained. Oxidative susceptibility of LDL, as determined by measuring the formation of conjugated dienes and the accumulation of cholesteryl ester hydroperoxides, was not higher in EPA/DHA-rich LDL. The oxLDL-induced cell apoptosis was detected by the activation of caspase-3, the translocation of PS to the outer surface of the plasma membrane using the Annexin V-fluorescein isothiocyanate binding assay, and the presence of chromatin condensation and nuclear fragmentation using the 4,6-diamidino-2-phenylindole staining assay. All three measures showed that after FO supplementation, EPA/DHA-rich oxLDL-induced cell apoptosis decreased. The decrease was not related to the concentration of lipid hydroperoxides. This study suggests that a possible protective effect of EPA/DHA-rich diets on atherosclerosis may be through lessening cell apoptosis in the arterial wall.
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PMID:Enrichment of LDL with EPA and DHA decreased oxidized LDL-induced apoptosis in U937 cells. 1237 50

The risk of atherosclerosis is intimately related to the heterogeneity of low-density lipoprotein (LDL) particles. The potential relationship between oxidative modification of distinct LDL subspecies and induction of apoptosis in arterial wall cells is indeterminate. The capacity of light LDL3 versus dense LDL5 to induce cytotoxicity in endothelial cells as a function of the degree of copper-mediated oxidation was compared. Mildly oxidized LDL3 (oxLDL3) exerted potent cytotoxicity, which was intimately related to both the degree of oxidation and the oxLDL3 concentration based on either cholesterol content or particle number. In contrast, dense LDL5 particles exerted a minor effect on cell viability. Cells incubated with oxLDL3 exhibited apoptotic features, with cytoplasmic condensation, cell or nuclear fragmentation, and accumulation of DNA fragments. OxLDL3-induced apoptosis involved cytoplasmic release of cytochrome c, with a concomitant increase in caspase-3-like protease activity. OxLDL3 particles were uniquely distinct from oxLDL5 particles in their elevated content of lipid hydroperoxides. Hydroperoxide removal by NaBH4 markedly reduced oxLDL3-induced cytotoxicity, leading to an increase in cell viability. Lipid hydroperoxide content of oxidatively modified LDL subclasses is therefore a major determinant of the induction of apoptosis in endothelial cells. These data are highly relevant to atherogenic hypercholesterolemia, in which the LDL phenotype is dominated by elevated concentrations of light LDL3.
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PMID:Mildly oxidized LDL particle subspecies are distinct in their capacity to induce apoptosis in endothelial cells: role of lipid hydroperoxides. 1247 9

Two phenotypes of rat carotid arterial smooth muscle cells (SMC) have been isolated in our laboratory, and their proteolytic and anti-proteolytic activities have been investigated in the presence or absence of various stimulating agents. We report here a comparative study of the cytotoxic effects of nitric oxide (NO) donors, sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP), towards the swirling-type and the epithelioid-type SMCs. The concentration- and time-dependence of NO donors' capacity to induce cell deaths was measured by an intracellular acid phosphatase activity assay and cell counting. The typical morphological features of apoptosis, such as cell blebbing and cytoplasm condensation, were observed by phase contrast microscopy and with a fluorescent DNA-binding dye. Apoptotic cell deaths were confirmed using DNA fragmentation and terminal deoxyribonucelotidyl transferase-mediated dUTP nick end labelling (TUNEL) methods. Western blots were used to investigate the protein expression of several known mediators of apoptosis. It was found that both NO donors induced cell deaths in the SMC phenotypes. Compared to the swirling SMCs, the epithelioid SMCs were much more sensitive to these agents. A time- and dose-dependent decrease of cell viability was observed at NO donor concentrations higher than 0.2 mmol/l. Microscopic methods revealed cell morphology of apoptotic cell deaths. The 180-bp DNA multimers typical of apoptosis were shown by DNA fragmentation. TUNEL technique confirmed that apoptosis occurred most readily in the epithelioid SMCs than the swirling SMCs. When epithelioid SMCs were treated with SNP, changes in p53, p21(WAF1), Bcl-2, caspase 3 and PARP protein expression were found. These protein levels were unchanged when swirling SMCs were similarly treated.
Atherosclerosis 2003 Feb
PMID:Cytotoxicity of nitric oxide donors in smooth muscle cells is dependent on phenotype, and mainly due to apoptosis. 1253 34

There is substantial evidence that cytokines induce apoptosis of vascular smooth muscle cells (VSMCs) in atherosclerosis. Its regulation, however, is not completely defined. The aim of this study is to investigate whether proteasome activity is related with apoptosis in VSMCs by tumor necrosis factor-alpha (TNF-alpha). Rat aorta smooth muscle cells were treated with TNF-alpha and proteasome inhibitor MG132 and then cell death was determined by morphology, viability, and DNA fragmentation. MG132 or TNF-alpha alone did not induce cell death. In contrast, co-treatment of TNF-alpha and proteasome inhibitor induced death and DNA degradation in VSMCs, suggesting proteasome inhibitor enhanced death activity of TNF-alpha. The death was not blocked by ascorbic acid but by nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine. Both caspase-3 and -8 were activated during the death by the proteasome inhibitor and TNF-alpha. The death was effectively blocked by the caspase-3 inhibitor z-DEVD-fmk, suggesting a role of caspase-3 in the death. Nonetheless, there were no significant alterations in the level of Bcl-2, Bcl-X(L), Bax and Bak by the proteasome inhibitor, nor any evidence of cytochrome (cyt) c release into cytosol from dying cells, suggesting that cyt c is not involved. These results suggest that proteasome inhibition potentiates TNF-mediated death in VSMCs in a cyt c-independent pathway. The present study proposes a new mechanism by which VSMCs undergo death by cytokines.
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PMID:Enhancement of TNF-alpha-mediated cell death in vascular smooth muscle cells through cytochrome c-independent pathway by the proteasome inhibitor. 1256 Jan 2

Apoptosis of vascular endothelial cells (VECs) and concomitant proliferation of the underlying vascular smooth muscle cells (VSMCs) in large arteries are the key features of atherosclerosis and restenosis. However, the mechanisms underlying endothelial cell death and abnormal smooth muscle cell proliferation during the development of vascular lesions remain unclear. We have previously demonstrated that treatment with inhibitors of the aldehyde-metabolizing enzyme and aldose reductase (AR) attenuates restenosis of balloon-injured rat carotid arteries. The inhibition of AR also prevents the apoptosis of VECs induced by the tumor necrosis factor-alpha (TNF-alpha). Apoptosis of the VECs was determined by the incorporation of [3H]-thymidine and the activation of caspase-3. Stimulation of the VECs with TNF-alpha led to an increase in the DNA-binding activity of the transcription factor, nuclear factor-kappa binding protein (NF-kappaB) and the induction of the adhesion molecule (ICAM)-1. Treatment of VECs with the AR inhibitor, tolrestat, prevented the activation of NF-kappaB and diminished ICAM-1 induction stimulated by TNF-alpha. These results indicate an obligatory requirement of AR activity in the transduction of intracellular signaling initiated by the ligation of the TNF-alpha receptors leading to the activation of NF-kappaB. Although the specific signaling events interrupted by AR inhibition remain unknown, our results suggest that product(s) of AR catalysis may be essential for NF-kappaB activation. These observations could form the basis of future investigations into the therapeutic utility of AR inhibitors in preserving endothelial function and integrity during atherosclerosis and diabetes.
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PMID:Role of aldose reductase in TNF-alpha-induced apoptosis of vascular endothelial cells. 1260 46

Plasminogen activator inhibitor-1 (PAI-1) and two-chain high molecular weight kininogen (HKa) exert anti-adhesive properties in vitronectin-dependent cell adhesion. Here, the hypothesis was tested that these anti-adhesive components promote apoptosis in vascular cells. PAI-1 or HKa induced a 2- to 3-fold increase in apoptosis of human umbilical-vein endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC) adherent to vitronectin, as determined by annexin V-FACS assay, similar to alphav-integrin inhibitor cyclo-(Arg-Gly-Asp-D-Phe-Val)-peptide (cRGDfV). Apoptosis occurred after 12 h incubation and was attributable to caspase 3 activation that in turn induced DNA fragmentation. Induction of apoptosis strongly correlated with the anti-adhesive effect of PAI-1 and HKa on these cells. In contrast, PAI-1 and HKa did not affect fibronectin-dependent adhesion or cell survival. uPA did not influence apoptosis in vitronectin- or fibronectin-adherent cells. In atherosclerotic vessel sections, congruent distribution of vitronectin, PAI-1, HK, and of components of the urokinase plasminogen activator/receptor system with apoptotic cells lining foam cell lesions was demonstrated by immunostaining. These results indicate that inhibition of vitronectin-dependent cell adhesion through PAI-1 and HKa correlates with apoptosis induction in vascular cells mediated through the caspase 3 pathway. Co-distribution of apoptosis with plasminogen activation system components in atherosclerosis exemplifies the significance of anti-adhesive mechanisms and apoptosis for tissue remodeling, such as in neointima development.
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PMID:Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties. 1271 93

Endothelial cell apoptosis can be initiated by withdrawing growth factors or serum, and is inhibited by HDL. Our results show that the total lipoprotein population from apolipoprotein E 4/4 (APOE4/4) sera is less anti-apoptotic than total lipoproteins from other APOE genotypes, as measured by caspase 3/7 activity. Moreover, APOE4/4 VLDL antagonizes the antiapoptotic activity of HDL by a mechanism requiring binding of apoE4 on VLDL particles to an LDL family receptor. This ability of APOE4/4 VLDL to inhibit the antiapoptotic effects of HDL presents a potential mechanism by which the expression of several diseases, including atherosclerosis, is enhanced by the APOE4 genotype.
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PMID:ApoE genotype-specific inhibition of apoptosis. 1275 78

Oxidized low-density lipoprotein (oxLDL) is known to induce apoptosis in endothelial cells, and this is believed to contribute to the progression of atherosclerosis. In the present study we made the novel observation that oxLDL-induced death of HMEC-1 cells is accompanied by activation of calpain. The mu-calpain inhibitor PD 151746 decreased oxLDL-induced cytotoxicity, whereas the general caspase inhibitor BAF (t-butoxycarbonyl-Asp-methoxyfluoromethylketone) had no effect. Also, oxLDL provoked calpain-dependent proteolysis of cytoskeletal alpha-fodrin in the HMEC-1 cells. Our observation of an autoproteolytic cleavage of the 80 kDa subunit of mu-calpain provided further evidence for an oxLDL-induced stimulation of calpain activity. The Bcl-2 protein Bid was also cleaved during oxLDL-elicited cell death, and this was prevented by calpain inhibitors, but not by inhibitors of cathepsin B and caspases. Treating the HMEC-1 cells with oxLDL did not result in detectable activation of procaspase 3 or cleavage of PARP [poly(ADP-ribose) polymerase], but it did cause polyubiquitination of caspase 3, indicating inactivation and possible degradation of this protease. Despite the lack of caspase 3 activation, oxLDL treatment led to the formation of nucleosomal DNA fragments characteristic of apoptosis. These novel results show that oxLDL initiates a calpain-mediated death-signalling pathway in endothelial cells.
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PMID:Oxidized low-density lipoprotein induces calpain-dependent cell death and ubiquitination of caspase 3 in HMEC-1 endothelial cells. 1277 16

Oxidized phospholipids, including 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), typically present in minimally modified low density lipoprotein, have been found in atherosclerotic lesions. These compounds are gaining increasing importance as inducers of different cellular responses (inflammation, proliferation, or cell death). It was the aim of this study to understand their impact on intracellular signal transduction pathways that are responsible for these biological effects. We found that in arterial smooth muscle cells, PGPC and POVPC activated sphingomyelinases, in particular the acid isoform, which is known to participate in the very early phase of apoptotic stress responses. In addition, mitogen-activated protein kinases, which are involved in induction of stress response and apoptosis were phosphorylated (activated). Finally, activation of caspase 3 was observed, showing that stimulation of smooth muscle cells with POVPC and PGPC is associated with apoptosis. Stimulation of all these enzymes by the oxidized phospholipids almost perfectly matched their activation by minimally modified LDL. Consequently, these phospholipids seem to be responsible for the effect of this particle on cell signaling. Survival and proliferation pathways including NF-kappa B or AKT kinase were not induced by POVPC and PGPC. Experiments with a specific inhibitor of acid sphingomyelinase named NB6 showed that this enzyme plays a central role in mediating the apoptotic effects of the oxidized lipids. Thus, we conclude that modified phospholipids induce signaling cascades via activation of acid sphingomyelinase finally leading to apoptosis of smooth muscle cells, which is a detrimental process in the development of atherosclerosis.
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PMID:Oxidized phospholipids in minimally modified low density lipoprotein induce apoptotic signaling via activation of acid sphingomyelinase in arterial smooth muscle cells. 1281 58

Magnolol, an active component extracted from Magnolia officinalis, has various pharmacological effects, including potent antioxidant activity. In the present study, we investigated the effect of magnolol on apoptosis in rat vascular smooth muscle cells (VSMCs), using terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) and flow cytometric analysis. Magnolol (5-20 micro M) concentration-dependently induced significant VSMC apoptosis, this effect being blocked by the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk, 50 micro M). To study the molecular mechanism, the mitochondrial death pathway was examined. Magnolol increased caspase-3 and caspase-9 activities significantly and reduced the mitochondrial potential (Deltapsi(m)). The levels of B-cell leukaemia/lymphoma-2 (Bcl-2), but not those of Bcl-2-associated X protein (Bax) or Bcl-x(L), were down-regulated concentration dependently by magnolol. In an animal model, balloon angioplasty-induced neointima formation was inhibited significantly by magnolol and Bcl-2 protein levels were reduced. Taken together, these results show that magnolol induces apoptosis in VSMCs via the mitochondrial death pathway. This effect is mediated through down-regulation of Bcl-2 protein levels, both in vivo and in vitro. Magnolol thus shows potential as a novel therapeutic agent for the treatment of atherosclerosis and re-stenosis.
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PMID:Magnolol induces apoptosis in vascular smooth muscle. 1289 28


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