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)

Diabetes is a major risk factor for atherosclerosis. Hyperglycemia is an underlying contributing factor; however, the mechanisms that mediate the vascular complications are not yet fully understood. In the present study, we provide evidence that elevated glucose induces discordant matrix metalloproteinase (MMP) expression from two key vascular cells, endothelial cells and macrophages. Our results clearly indicate that high glucose (25 mM) induced endothelial cell expression and activity of the collagenase, MMP-1 and the gelatinase, MMP-2, whilst reducing expression of the stromelysin, MMP-3 (P<0.05). Similarly, our results show that high glucose (25 mM) induces expression and activity of MMP-9 from monocyte-derived macrophages (P<0.05). High glucose culture did not affect metalloproteinase inhibitor (TIMP-1) expression. Our results suggest for the first time that high glucose exposure induced discordant regulation of the MMP/TIMP system in vascular cells. The increased MMP-1, MMP-2 and MMP-9 activities induced by high glucose exposure could promote matrix degradation thereby accelerating atherogenesis and potentially reducing plaque stability in diabetes.
Atherosclerosis 2003 Jun
PMID:High glucose alters matrix metalloproteinase expression in two key vascular cells: potential impact on atherosclerosis in diabetes. 1280 9

The proteolytic activity of proinflammatory matrix metalloproteinases (MMPs) is elevated in lipid-rich atherosclerotic plaques, thereby contributing to plaque fragility and rupture. We hypothesized that changes in circulating levels of MMPs and their specific inhibitors (TIMPs) could reflect the atherosclerotic process occurring within the arterial wall. We determined serum levels of MMP-3, MMP-9, TIMP-1 and TIMP-2 in dyslipidemic subjects and compared them to those of age- and sex-matched normolipidemic healthy controls. Serum levels of MMP-3, MMP-9 and TIMP-1 were significantly increased in hyperlipidemic subjects versus controls (+54, +29 and +15%, respectively; P<0.001). We also noted a trend to elevated serum MMP-3 levels in patients with atherosclerotic lesions when compared to patients free of atherosclerosis (P=0.07). Circulating levels of MMPs and TIMPs were associated neither with those of C-reactive protein, nor with those of alpha2-macroglobulin (a nonspecific MMP inhibitor), nor with intima-media thickness values. Nonetheless, when divided into tertiles, MMP-3 and TIMP-1 levels in the highest tertile were positively associated with the presence of carotid artery lesions (odds ratios=3.4 and 2.0, confidence intervals 1.7-13.9 and 1.3-7.9, respectively). Thus, serum levels of MMP-3, -9 and TIMP-1 are significantly elevated in asymptomatic hyperlipidemic subjects at high cardiovascular risk; however, MMP-3 and TIMP-1 levels are strongly positively associated with the presence of carotid lesions. Such elevations might reflect enhanced vascular matrix remodeling, a key feature of the progression of atherosclerotic disease.
Atherosclerosis 2003 Jul
PMID:Serum matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 as potential markers of carotid atherosclerosis in infraclinical hyperlipidemia. 1286 Feb 60

Genetic factors that determine the degree of susceptibility to atherosclerosis may also influence the effects of estrogens and progestins in arterial vessel disease. We examined and compared estrogen receptor (ER) and progesterone receptor (PR) expression and the effects of 17beta-estradiol (E2) and progesterone (P) on collagen synthesis and matrix metalloproteinase (MMP) activities in the aortic arch and in cultured aortic smooth muscle cells (ASMC) of atherosclerosis-susceptible (C57Bl6/J, B6) or -resistant (C3H/HeJ, C3H) mice. ERalpha, ERbeta, and PR levels were higher in the aorta and ASMC of atherosclerosis-susceptible B6 mice. In transfection studies using an estrogen response element-driven reporter plasmid, E2 elicited a >2-fold increase in luciferase activity in ASMC of B6 (B6-ASMC), which demonstrated the transcriptional activity of ER in atherosclerosis-susceptible cells. Importantly, the response of endogenous target genes to E2 and P was different in B6-ASMC and C3H-ASMC. E2 decreased collagen synthesis but had no effect on MMP activities in B6-ASMC. P decreased MMP-2 and MMP-9 activity in B6-ASMC. In contrast, E2 increased MMP-2 and decreased MMP-9 activity but had no effect on collagen synthesis in C3H-ASMC. P had no effect on collagen synthesis and MMP activity in C3H-ASMC. These differences in response to sex hormones may have important implications for women who receive hormone replacement therapy.
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PMID:Response to sex hormones differs in atherosclerosis-susceptible and -resistant mice. 1291 98

Cigarette smoking has been associated with an increase in the severity and prevalence of atherosclerosis in the abdominal aorta. To begin our investigation of this finding, we used an integrated approach combining gene expression profiling, protein analysis, cytokine measurements, and cytotoxicity determinations to examine molecular responses of cultured human aortic and coronary endothelial cells exposed to cigarette smoke condensate (CSC) and nicotine. Exposure of endothelial cells to CSC (30 and 60 microg/mL TPM) for 24 h resulted in minimal cytotoxicity, and the upregulation of genes involved in matrix degradation (MMP-1, MMP-8, and MMP-9), xenobiotic metabolism (HO-1 and CYP1A2), and downregulation of genes involved in cell cycle regulation (including TOP2A, CCNB1, CCNA, CDKN3). Exposure of cells to a high physiological concentration of nicotine resulted in few differentially expressed genes. Immunoblot analysis of proteins selected from genes shown to be differentially regulated by microarray analysis revealed similar responses. Finally, a number of inflammatory cytokines measured in culture media were elevated in response to CSC. Together, these results describe a complex proinflammatory response, possibly mediating the recruitment of leukocytes through cytokine signaling. Additionally, fibrous cap destabilization may be facilitated by matrix metalloproteinase upregulation.
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PMID:Matrix-degrading and pro-inflammatory changes in human vascular endothelial cells exposed to cigarette smoke condensate. 1450 Oct 29

Clonal selection has been proposed as a pathogenetic mechanism in various chronic diseases, such as scleroderma, hypertension, pulmonary fibrosis, interstitial fibrosis of the kidney, atherosclerosis, and uterine leiomyomatosis. We previously found that mesangial cells from ROP mice prone to develop glomerulosclerosis changed their phenotype in response to high glucose concentrations. Here, we investigate whether clonal selection might contribute to this phenotype change. We found that in ROP mice at least two distinct mesangial cell clones exist. They are characterized by a different length of the d(CA) repeat in the MMP-9 promoter and exhibit a significantly different gene expression profile. Exposure of ROP mesangial cells to 25 mmol/l glucose for 35 days induces both clonal selection and reversible dinucleotide repeat expansion. None of these findings were present in mesangial cells isolated from C57BL/6 mice, which are not sclerosis-prone. We conclude that mesangial cell michrochimerism may be a marker for the susceptibility to glomerulosclerosis, that dinucleotide repeat expansion may be a novel mechanism for glucose-induced changes in gene expression, and that clonal selection may partially explain the change in mesangial cell phenotype in diabetes.
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PMID:Glucose induces clonal selection and reversible dinucleotide repeat expansion in mesangial cells isolated from glomerulosclerosis-prone mice. 1451 45

The PPAR gamma agonists, thiazolidinediones (TZDs), have anti-inflammatory properties as well as increasing insulin sensitivity. This has widened their therapeutic scope to treat inflammatory diseases such as atherosclerosis in addition to Type 2 Diabetes. TZDs are known to reduce monocyte/macrophage expression of Matrix metalloproteinase (MMP)-9, which is implicated in atherosclerotic plaque destabilization. This study aims to identify other metalloproteinase genes of the ADAM (A Disintegin And Metalloproteinase) and ADAMTS families that are regulated by PPAR gamma or RXR agonists, which are potentially important in type 2 diabetes and/or related atherosclerosis. The synthetic PPAR gamma agonist, GW7845, and the natural agonist 15d-PGJ2, suppressed PMA stimulated MMP-9 in human monocyte-like cells (THP-1) only in the presence of 9-cis-retinoic acid. Quantitative Real-Time PCR showed that this reduction was regulated at the mRNA level. Expression of ADAMs 8, 9, and 17 were increased, and ADAM15 was decreased by stimulation of THP-1 with PMA, although these ADAMs were not regulated by PPAR gamma or RXR agonists. PMA-induced ADAM28 expression was further enhanced by the addition of 9-cis-retinoic acid. ADAMTS4, implicated in rheumatoid arthritis, was expressed in THP-1 cells, and significantly increased after 24 h of PMA stimulation. ADAMTS4 expression was suppressed by both PPAR gamma and RXR agonists and was undetectable when the agonists were combined. Pretreatment of THP-1 cells with the PPAR gamma antagonist, GW9662, suggests that PPAR gamma plays subtly different roles in the regulation of MMP-9, ADAMTS4 and ADAM28 gene expression. These results indicate that PPAR gamma and RXR agonists have complex effects on monocyte metalloproteinase expression, which may have implications for therapeutic strategies.
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PMID:Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid. 1453 4

Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE-/-OPN+/+, ApoE-/-OPN+/-, and ApoE-/-OPN-/- mice were infused with Ang II, inducing vascular OPN expression and accelerating atherosclerosis. Compared with ApoE-/-OPN+/+ mice, ApoE-/-OPN+/- and ApoE-/-OPN-/- mice developed less Ang II-accelerated atherosclerosis. ApoE-/- mice transplanted with bone marrow derived from ApoE-/-OPN-/- mice had less Ang II-induced atherosclerosis compared with animals receiving ApoE-/-OPN+/+ cells. Aortae from Ang II-infused ApoE-/-OPN-/- mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate, recruitment of leukocytes in OPN-/- mice was impaired, and OPN-/- leukocytes exhibited decreased basal and MCP-1-directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II-infused ApoE-/-OPN-/- mice was decreased. Finally, Ang II-induced abdominal aortic aneurysm formation in ApoE-/-OPN-/- mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocyte-derived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation.
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PMID:Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. 1459 59

Calcific aortic valve stenosis (AS), the main heart valve disease in the elderly, is characterized by extensive remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) are upregulated in calcific AS and might modulate matrix remodeling. The regulatory mechanisms are unclear. As recent studies have suggested that calcific AS might result from an inflammatory process involving leukocyte invasion and activation, the present study aimed to elucidate the role of the pro-inflammatory cytokine interleukin (IL)-1 beta on MMP expression and cell proliferation in human aortic valves. Immunohistochemistry for leukocytes, IL-1 beta and MMP-1 was performed on aortic valves with (n=6) and without (n=6) calcification obtained at valve replacement or autopsy. Stenotic valves showed marked leukocyte infiltration and associated expression of IL-1 beta and MMP-1. In control valves only scattered leukocytes, low staining for MMP-1 and no staining for IL-1 beta were present. Double-label immunostaining localized IL-1 beta expression mainly to leukocytes and MMP-1 expression to myofibroblasts. Stimulation of cultured human aortic valve myofibroblasts with IL-1 beta lead to a time-dependently increased expression of MMP-1 and MMP-2 by Western blotting and zymography, whereas MMP-9 remained unchanged. Cell proliferation was increased by IL-1 beta as determined by bromodesoxyuridine incorporation. Thus, IL-1 beta may regulate remodeling of the extracellular matrix in calcific AS.
Atherosclerosis 2003 Oct
PMID:Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. 1461 99

Non-invasive measurement of matrix metalloproteinase (MMP) activity in vivo is a clinical challenge in many disease processes such as inflammation, tumor metastasis and atherosclerosis. Therefore, radioiodinated analogues of the non-peptidyl broad-spectrum MMP inhibitor (MMPI) CGS 27023A 1a were synthesized for non-invasive detection of MMP activity in vivo using single photon emission computed tomography (SPECT). The compounds Br-CGS 27023A 1b and HO-CGS 27023A 1d were synthesized from the amino acid D-valine and used as precursors for radioiodinated derivatives of CGS 27023A and their non-radioactive references I-CGS 27023A 1c and HO-I-CGS 27023A 1e. Radioiodination of the precursors with [(123)I]NaI or [(125)I]NaI produced the no-carrier-added MMP inhibitors [(123)I]I-CGS 27023A 1f, [(125)I]I-CGS 27023A 1g, HO-[(123)I]I-CGS27023A 1h, and HO-[(125)I]I-CGS 27023A 1i. In vitro studies showed that the non-radioactive analogues of the MMP inhibitors exhibited affinities against gelatinase A (MMP-2) and gelatinase B (MMP-9) in the nanomolar range, comparable to the parent compound CGS 27023A. In vivo biodistribution using HO-[(125)I]I-CGS 27023A 1i in CL57 Bl6 mice showed rapid blood and plasma clearance and low retention in normal tissues. The preliminary biological evaluation warrant further studies of these radioiodinated MMP inhibitors as potential new radiotracers for imaging MMP activity in vivo.
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PMID:Synthesis and preliminary biological evaluation of new radioiodinated MMP inhibitors for imaging MMP activity in vivo. 1501 92

The expression of TWEAK (TNFSF12) and TweakR/Fn14 was detected in regions rich in macrophage/foam cells in atherosclerotic plaques. The role of TWEAK in monocytes in relation to atherogenesis was investigated by analyzing the cellular events induced by TWEAK in a human macrophage-like cell line, THP-1. TWEAK induced various molecular mediators of atherogenesis, such as IL-6, MCP-1, IL-8 and MMP-9, and the induction was augmented by interferon-gamma. TWEAK-induced activation of MMP-9 was mediated by activation of NF-kappaB. These results suggest that TWEAK is involved in atherosclerosis by inducing pro-inflammatory cytokines and extracellular matrix degrading enzymes, which reduce plaque stability.
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PMID:TWEAK can induce pro-inflammatory cytokines and matrix metalloproteinase-9 in macrophages. 1505 43


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