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)

Monocyte-derived macrophages (Mphis) are pivotal participants in the pathogenesis of atherosclerosis. Evidence from both animal and human plaques indicates that local proliferation may contribute to accumulation of lesion Mphis, and the major Mphi growth factor, macrophage colony stimulating factor (MCSF), is present in atherosclerotic plaques. However, most in vitro studies have failed to demonstrate that human monocytes/Mphis possess significant proliferative capacity. We now report that, although human monocytes cultured in isolation showed only limited MCSF-induced proliferation, monocytes cocultured with aortic endothelial cells at identical MCSF concentrations underwent enhanced (up to 40-fold) and prolonged (21 d) proliferation. In contrast with monocytes in isolation, this was optimal at low seeding densities, required endothelial cell contact, and could not be reproduced by coculture with smooth muscle cells. Intimal Mphi isolated from human aortas likewise showed endothelial cell contact-dependent, MCSF-induced proliferation. Consistent with a two-signal mechanism governing Mphi proliferation, the cell cycle regulatory protein, cyclin E, was rapidly upregulated by endothelial cell contact in an MCSFindependent fashion, but MCSF was required for successful downregulation of the cell cycle inhibitory protein p27(Kip1) before cell cycling. Thus endothelial cells and MCSF differentially and synergistically regulate two Mphi genes critical for progression through the cell cycle.
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PMID:Aortic endothelial cells regulate proliferation of human monocytes in vitro via a mechanism synergistic with macrophage colony-stimulating factor. Convergence at the cyclin E/p27(Kip1) regulatory checkpoint. 918 9

Arterial lesions in cardiovascular diseases are characterized by proliferation and migration of smooth muscle cells as well as deposition of connective tissue matrix. Factors that stimulate vascular smooth muscle cell (VSMC) proliferation are well described; however, the role of proteins that limit intimal hyperplasia is not well understood. To examine the function of Kip/Cip and INK cyclin-dependent kinase inhibitors (CKIs) in vascular diseases, the expression of p27Kip1 and p16INK was examined in VSMCs in vitro and in porcine arteries and human atherosclerosis in vivo. Western blot and fluorescence activated cell-sorting analysis demonstrated that levels of p27Kip1, but not p16INK, increased during serum deprivation of primary VSMC cultures and caused G1 arrest. p27Kip1 inhibited Cdk2 activity, suggesting that Kip CKIs promote G1 arrest in VSMCs by binding cyclin E/Cdk2. In porcine arteries, p27Kip1, but not p16INK, was constitutively expressed at low levels. Immediately after balloon injury, cell proliferation increased as p27Kip1 levels declined. Three weeks after injury, p27Kip1 was strongly expressed in intimal VSMCs when VSMC proliferation was < 2%, suggesting that p27Kip1 functions as an inhibitor of cell proliferation in injured arteries. In contrast, p16INK expression was detected only transiently early after injury. CKI expression was examined in 35 human coronary arteries, ranging from normal to advanced atherosclerosis. p27Kip1 expression was abundant in nonproliferating VSMCs and macrophages within normal (7 of 8) and atherosclerotic (25 of 27) arteries. p21Cip1 levels were undetectable in normal arteries but were elevated in atherosclerotic (19 of 27) arteries. p16INK could not be detected in normal or atherosclerotic arteries (0 of 35). Thus, the Kip/Cip and INK CKIs have different temporal patterns of expression in VSMCs in vitro and in injured arteries and atherosclerotic lesions in vivo. In contrast to p16INK, p27Kip1 likely contributes to the remodeling process in vascular diseases by the arrest of VSMCs in the G1 phase of the cell cycle.
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PMID:Expression of cyclin-dependent kinase inhibitors in vascular disease. 948 68

Chronic rejection of transplanted organs is manifested as atherosclerosis of the blood vessels of the allograft. HLA class I Ags have been implicated to play a major role in this process, since signaling via HLA class I molecules can induce the proliferation of aortic endothelial as well as smooth muscle cells. In this study, we show that HLA class I-mediated induction of cell proliferation correlates with inactivation of the Rb protein in the T cell line Jurkat as well as human aortic endothelial cells. HLA class I-mediated inactivation of Rb can be inhibited specifically by neutralizing Abs to basic fibroblast growth factor (bFGF), suggesting a role for FGF receptors in the signaling process. Signaling through HLA class I molecules induced cyclin E-associated kinase activity within 4 h in quiescent endothelial cells, and appeared to mediate the inactivation of Rb. A cdk2 inhibitor, Olomoucine, as well as a dominant-negative cdk2 construct prevented HLA class I-mediated inactivation of Rb; in contrast, dominant-negative cdk4 and cdk6 constructs had no effect. Furthermore, there was no increase in cyclin D-associated kinase activity upon HLA class I ligation, suggesting that cyclin E-dependent kinase activity mediates Rb inactivation, leading to E2F activation and cell proliferation.
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PMID:HLA class I-mediated induction of cell proliferation involves cyclin E-mediated inactivation of Rb function and induction of E2F activity. 1022 11

Atherosclerosis is a 'response-to-injury' process associated with chronic inflammation, tissue repair and a considerable cell turnover. These growth-related processes are controlled by the 'cell cycle clock' which is composed of cyclin-dependent kinases (Cdks), their activating subunits, the cyclins, and by inhibitors of Cdks (Ckis). P27 is a Cki which associates with cyclin A-Cdk2, cyclin D-Cdk4 and with cyclin E (CE)-Cdk2 complexes thereby abrogating their catalytic activity leading to potent inhibition of late G1 to S-phase transition. Furthermore, TGF-beta1 mRNA and immunoreactivity are locally increased in atherosclerotic lesions. Since TGF-beta1 growth suppressive function in the late G1 phase may be mediated by p27, blocking the catalytic activity of CE-Cdk2 complexes, via the stimulation of TGF-beta-RI and TGF-beta-RII, we investigated the topographical association between TGF-beta-RI, TGF-beta-RII, P27Kip1 and CE by immunohistochemistry in coronary artery segments without atherosclerosis and carotid atheromatous plaques of 11 patients undergoing carotid endarterectomy. P27-immunoreactivity was present in 11/11 atherosclerotic (92.7 +/- 3.3% of the cells) and 5/5 control (80.9 +/- 3.7% of the cells; P < 0.002 versus control) specimens and localized to nuclei of macrophages (CD68-positive), vascular smooth muscle cells (alpha-actin positive), T-lymphocytes (CD3-positive) as well as to the nuclei of endothelial cells. In the atherosclerotic tissue, TGF-beta-RI and TGF-beta-RII-immunoreactivity was present in 11/11 specimens and localized to inflammatory cells and to cells with VSMC-like-morphology. TGF-beta-RI-immunoreactivity was present in 87.4 +/- 5.3% (controls 75.3 +/- 7.48%; n.s.) and TGF-beta-RII-immunoreactivity was present in 83.7 +/- 6.8% (controls 39.5 +/- 7.3%; P < 0.002) of the cells. Double immunolabeling, and investigation of serial sections revealed co-expression of TGF-beta-RI and TGF-beta-RII in virtually all cells positive for P27. In the atherosclerotic specimens, CE-immunoreactivity was present in all specimens in macrophages (CD68-positive), vascular smooth muscle cells (alpha-actin positive) and in endothelial cells in 12.58 +/- 13.58% of the nuclei whereas in the controls CE staining was restricted to 0.19 +/- 0.43% of the cells (P < 0.001). Importantly, as shown by immunofluorescent double-labeling, we found cells expressing P27 that were simultaneously positive for CE. In summary, the present study provides evidence that TGF-beta1 present in human atherosclerotic tissue may mediate its growth suppressive activity also by p27, blocking the activity of CE-Cdk2 complexes. Quantitative analysis revealed that TGF-beta-RII, p27 and CE are concordantly upregulated in the atherosclerotic tissue with chronic inflammation, supporting the view that TGF-beta1, p27 and CE may play an important role in the processes associated with chronic inflammation and cell turnover in advanced human atherosclerotic plaques. Taken together, these results provide a possible link between the chronic inflammation associated with advanced atherosclerosis, the effects of extracellular growth factors and cell cycle control.
Atherosclerosis 1999 May
PMID:Concordant upregulation of type II-TGF-beta-receptor, the cyclin-dependent kinases inhibitor P27Kip1 and cyclin E in human atherosclerotic tissue: implications for lesion cellularity. 1038 Dec 72

The thiazolidenediones (TZDs) are commonly used to treat hyperglycemia in type 2 diabetes. Diabetes is associated with macrovascular disease, leading to accelerated atherosclerosis caused by aberrant vascular smooth muscle (VSM) cell proliferation. Although VSM cell proliferation is inhibited by the TZDs, the mechanism of this effect has not been established. Because of reports that the cyclin kinase inhibitors (CKIs) p21(Waf1/Cip1) and p27(Kip1) can exhibit both growth-inhibitory and growth-permissive effects in VSM cells, we asked whether alterations in these cell cycle regulatory proteins are the mechanism by which the TZDs inhibit VSM cell growth. We show that platelet-derived growth factor-BB increases p21 and p27 and that this increase is attenuated by TZDs. Surprisingly, when VSM cells were transfected with antisense oligodeoxynucleotides to p21 and p27, inhibition of DNA synthesis by TZDs occurred to the same degree as in control cells. Furthermore, the TZDs have inhibitory effects on cyclin D1 and cyclin E levels, suggesting another mechanism by which these drugs decrease VSM cell growth. These data suggest that the TZD-mediated reduction in CKI levels is not the sole mechanism for their antiproliferative effects. The observed decrease in levels of the G1 cyclins by the TZDs suggests a possible mechanism of VSM cell growth inhibition.
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PMID:TZDs inhibit vascular smooth muscle cell growth independently of the cyclin kinase inhibitors p21 and p27. 1144 Aug 95

Pyrrolidine dithiocarbamate (PDTC), a metal chelating compound, is known to induce cell death in vascular smooth muscle cells (VSMC). However, the molecular mechanism for PDTC-induced VSMC death is not well understood. Addition of PDTC reduced cell growth and DNA synthesis on VSMC in low density conditions. However, in serum depleted medium, PDTC did not affect the cell viability, suggesting that certain factors in serum may mediate the cytotoxic effect of PDTC. Several metal chelators prevented the cell death induced by PDTC. In a serum-deprived condition, addition of exogenous metals, copper, iron, and zinc, restored the cytotoxic effect of PDTC. These data indicate that metals such as copper, iron, and zinc in serum may mediate the cytotoxic effect of PDTC. At low VSMC density in 10% FBS, treatment of PDTC, which induced a cell-cycle block in G1-phase, induced down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 expression, whereas up-regulation of p27 or p53 by PDTC was not observed. Finally, we determined PDTC-mediated signaling pathway involved in VSMC death. Among relevant pathways, PDTC induced marked activation of p38MAPK and JNK. Expression of dominant negative p38MAPK and SB203580, a p38MAPK specific inhibitor, blocked PDTC-dependent p38MAPK, growth inhibition, and p21 expression. These data demonstrate that the p38MAPK pathway participates in p21 induction, which consequently leads to decrease of cyclin D1/cdk4 and cyclin E/cdk2 complexes and PDTC-dependent VSMC growth inhibition. In conclusion, an understanding of the molecular mechanisms of PDTC in VSMC provides a theoretical basis for clinical approaches using antioxidant therapies in atherosclerosis.
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PMID:PDTC, metal chelating compound, induces G1 phase cell cycle arrest in vascular smooth muscle cells through inducing p21Cip1 expression: involvement of p38 mitogen activated protein kinase. 1460 33

Several genes are regulated by tocopherols which can be categorized, based on their function, into five groups: genes that are involved in the uptake and degradation of tocopherols (Group 1) include alpha-tocopherol transfer protein (alpha-TTP) and cytochrome P450 (CYP3A); genes that are associated with lipid uptake and atherosclerosis (Group 2) include CD36, SR-BI and SR-AI/II. Genes that modulate the expression of extracellular proteins (Group 3) include tropomyosin, collagen(alpha1), MMP-1, MMP-19 and connective tissue growth factor (CTGF). Genes that are related to inflammation, cell adhesion and platelet aggregation (Group 4) include E-selectin, ICAM-1, integrins, glycoprotein IIb, II-2, IL-4 and IL-beta. Group 5 comprises genes coding for proteins involved in cell signaling and cell cycle regulation and consists of PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27 and CD95 (Apo-1/Fas ligand). The expression of P27, Bcl2, alpha-TTP, CYP3A, tropomyosin, II-2, PPAR-gamma, and CTGF appears to be up-regulated by one or more tocopherols whereas all other listed genes are down-regulated. Several mechanisms may underlie tocopherol-dependent gene regulation. In some cases protein kinase C has been implicated due to its deactivation by alpha-tocopherol and its participation in the regulation of a number of transcription factors (NF-kappaB, AP-1). In other cases a direct involvement of PXR/RXR has been documented. The antioxidant responsive element (ARE) appears in some cases to be involved as well as the transforming growth factor beta responsive element (TGF-beta-RE). This heterogeneity of mediators of tocopherol action suggests the need of a common element that could be a receptor or a co-receptor, able to interact with tocopherol and with transcription factors directed toward specific regions of promoter sequences of sensitive genes. Here we review recent results of the search for molecular mechanisms underpinning the central signaling mechanism.
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PMID:Regulation of gene expression by alpha-tocopherol. 1531 6

alpha-Tocopherol modulates two major signal transduction pathways centered on protein kinase C and phosphatidylinositol 3-kinase. Changes in the activity of these key kinases are associated with changes in cell proliferation, platelet aggregation, and NADPH-oxidase activation. Several genes are also regulated by tocopherols partly because of the effects of tocopherol on these two kinases, but also independently of them. These genes can be divided in five groups: Group 1. Genes that are involved in the uptake and degradation of tocopherols: alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine synthetase heavy subunit, and glutathione-S-transferase. Group 2. Genes that are implicated with lipid uptake and atherosclerosis: CD36, SR-BI, and SR-AI/II. Group 3. Genes that are involved in the modulation of extracellular proteins: tropomyosin, collagen-alpha-1, MMP-1, MMP-19, and connective tissue growth factor. Group 4. Genes that are connected to adhesion and inflammation: E-selectin, ICAM-1 integrins, glycoprotein IIb, IL-2, IL-4, IL-1b, and transforming growth factor-beta (TGF-beta). Group 5. Genes implicated in cell signaling and cell cycle regulation: PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27, CD95 (APO-1/Fas ligand), and 5a-steroid reductase type 1. The transcription of p27, Bcl2, alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine sythetase heavy subunit, tropomyosin, IL-2, and CTGF appears to be upregulated by one or more tocopherols. All the other listed genes are downregulated. Gene regulation by tocopherols has been associated with protein kinase C because of its deactivation by alpha-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, AP1). A direct participation of the pregnane X receptor (PXR) / retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element (TGF-beta-RE) appear in some cases to be implicated as well.
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PMID:Vitamin E mediates cell signaling and regulation of gene expression. 1575 36

Several antioxidant enzymes, including copper, zinc-superoxide dismutase (Cu, Zn-SOD) and catalase, have been suggested to be protective against the proliferation of vascular smooth muscle cells exposed to oxidative stress. In the present study, we investigated effects of Cu, Zn-SOD and/or catalase on oxLDL-induced proliferation of, and intracellular signaling in, human aortic smooth muscle cells (HASMCs). HASMCs were transfected with adenovirus carrying the human Cu, Zn-SOD gene and/or the human catalase gene. This resulted in a high level of Cu, Zn-SOD and/or catalase overexpression and decreased oxLDL-induced proliferation. Cu, Zn-SOD and/or catalase also arrested cell cycle progression, which was associated with decreased expression of cyclin D1, cyclin E, CDK2, and CDK4 and upregulation of p21(Cip1) and p27(Kip1). Phosphorylation studies on ERK1/2, JNK, and p38, three major subgroups of mitogen activator protein kinases, demonstrated that Cu, Zn-SOD and/or catalase overexpression suppressed ERK1/2 and JNK phosphorylation. Gel-mobility shift analysis showed that oxLDL caused an increase in the DNA binding activity of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), which was inhibited by Cu, Zn-SOD and/or catalase overexpression. These results provide the first evidence that overexpression of Cu, Zn-SOD and/or catalase in HASMCs attenuates the cell proliferation caused by oxLDL stimulation and that this inhibitory effect is mediated via downregulation of ERK1/2 and JNK phosphorylation and AP-1 and NF-kappaB inactivation. These observations support the feasibility of the increase of Cu, Zn-SOD and/or catalase expression in human smooth muscle cells as a means of protection against oxidant injury.
Atherosclerosis 2007 Jan
PMID:Superoxide dismutase and catalase inhibit oxidized low-density lipoprotein-induced human aortic smooth muscle cell proliferation: role of cell-cycle regulation, mitogen-activated protein kinases, and transcription factors. 1660 Feb 49

Morbidity and mortality from atherosclerosis are associated with complicated atherosclerotic lesions due to plaque rupture, which is regulated by a balance between proliferation and apoptosis of vascular smooth muscle cells (VSMC). We examined insulin-like growth factor-1 (IGF-1)-induced survival of plaque VSMC from carotid endarterectomy specimens and investigated the underlying cellular mechanisms in the presence and absence of IL-12 and IFN-gamma. Both IL-12 and IFN-gamma were strongly expressed in symptomatic atherosclerotic plaques as compared with asymptomatic plaques. In asymptomatic plaque VSMC, IGF-1 induced the survival and proliferation of VSMC and accelerated VSMC into S-phase. IL-12 or IFN-gamma inhibited proliferation and VSMC were arrested in the G0-G1 phase. IGF-1 markedly inhibited the expression of p27(kip) and p21(cip) and significantly induced cyclin E and cyclin D. Both cytokines by themselves increased the expression of p27(kip) and p21(cip) and inhibited cyclin E and cyclin D. On the contrary, in symptomatic VSMC there was already increased apoptosis of VSMC and there was no significant effect of IGF-1 or inflammatory cytokines on proliferation, apoptosis or the expression of p27(kip) and p21(cip) and cyclin D and E. These data suggest that IGF-1 is more potent in inducing the survival of VSMC from the endarterectomy specimens of asymptomatic patients as compared to that of symptomatic subjects and cytokines associated with atheroma lesions decrease the activity of IGF-1-induced survival in the VSMC of asymptomatic plaques. The different expression and activity of cell cycle regulatory proteins could be responsible for apoptosis of VSMC and destabilization of atherosclerotic plaques.
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PMID:Differential effects of insulin-like growth factor-1 and atheroma-associated cytokines on cell proliferation and apoptosis in plaque smooth muscle cells of symptomatic and asymptomatic patients with carotid stenosis. 1694 85


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