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)

Leptin, the product of ob gene, is an endocrine hormone that regulates adipose tissue mass. Recently, leptin has been found to generate a growth signal involving a tyrosine kinase-dependent intracellular pathway and promote angiogenic processes via activation of leptin receptor (Ob-R) in endothelial cells. However, it is not clear how leptin functions to promote multi-step processes involved in the neovascularization at the atherosclerotic plaque. We have examined the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and Ob-R in human atherosclerotic lesions, leptin-mediated angiogenesis in vivo and in vitro. Immunohistochemical analysis of human atherosclerotic aorta revealed an increased expression of Ob-R in the intima of neorevascularized regions and of both MMPs and TIMPs predominantly in the endothelial lining of intimal neovessels and macrophages/foam cells. In the rat corneal angiogenesis assay, leptin elicited a comparable sensitivity of angiogenic activity to those of vascular endothelial growth factor (VEGF). The immunohistological analysis of the leptin-treated rat cornea showed definitive rises in Ob-R, MMPs and TIMPs expression as well as those of VEGF receptor (VEGFR-1). Leptin (10-40 ng/ml) induced proliferation of the human umbilical vein endothelial cells (HUVECs) and elevation of MMP-2, MMP-9, TIMP-1, and TIMP-2 expression in a dose-dependent manner. Leptin also induced increases of MMP-2, MMP-9, TIMP-1, and Up-regulated the human coronary artery smooth muscle cells (HCASMCs). These findings suggest that leptin, a hormone with pluralistic properties including a mitogenic activity on vascular endothelial cells, plays a role in matrix remodeling by regulating the expression of MMPs and TIMPs. Taken together, our findings further provide evidences for leptin's role as an angiogenesis inducer in the normal organ (rat cornea) and in aberrant vasculature under duress like atherosclerosis.
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PMID:Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. 1146 Aug 88

Increased activity of matrix metalloproteinases (MMPs) has been implicated in numerous disease processes, including tumor growth and metastasis, arthritis, and periodontal disease. It is now becoming increasingly clear that extracellular matrix degradation by MMPs is also involved in the pathogenesis of cardiovascular disease, including atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction. Administration of synthetic MMP inhibitors in experimental animal models of these cardiovascular diseases significantly inhibits the progression of, respectively, atherosclerotic lesion formation, neointima formation, left ventricular remodeling, pump dysfunction, and infarct healing. This review focuses on the role of MMPs in cardiovascular disease, in particular myocardial infarction and the subsequent progression to heart failure. MMPs, which are present in the myocardium and capable of degrading all the matrix components of the heart, are the driving force behind myocardial matrix remodeling. The recent finding that acute pharmacological inhibition of MMPs or deficiency in MMP-9 attenuates left ventricular dilatation in the infarcted mouse heart led to the proposal that MMP inhibitors could be used as a potential therapy for patients at risk for the development of heart failure after myocardial infarction. Although these promising results encourage the design of clinical trials with MMP inhibitors, there are still several unresolved issues. This review describes the biology of MMPs and discusses new insights into the role of MMPs in several cardiovascular diseases. Attention will be paid to the central role of the plasminogen system as an important activator of MMPs in the remodeling process after myocardial infarction. Finally, we speculate on the use of MMP inhibitors as potential therapy for heart failure.
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PMID:Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? 1148 70

Vascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes requiring cell migration and degradation of extracellular matrix (ECM). Two proteolytic systems, the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems can degrade most ECM components. The availability of mice models with deficiency of main components of both systems has allowed to study their contribution to vascular remodeling in several biological processes. In mouse models of atherosclerosis, urokinase-mediated plasmin generation plays a role in activation of several macrophage-derived MMPs (MMP-3, -9, -12 and -13), triggering elastolysis and collagenolysis, resulting in media destruction and aneurysm formation. Neointima formation after vascular injury, a process that depends on smooth muscle cell migration, is reduced in mice with plasminogen or urokinase deficiency and enhanced in mice with deficiency of TIMP-1 (type 1 tissue inhibitor of MMPs). Also in allograft transplant arteriosclerosis and in abdominal aortic aneurysm both proteolytic systems contribute to matrix degradation. In a mouse model of myocardial infarction, urokinase deficiency protects totally and MMP-9 deficiency partially against cardiac rupture, but these animals suffer cardiac failure. Thus, the plasminogen/plasmin and MMP systems, in concert, contribute to vascular remodeling in the setting of cardiovascular disease.
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PMID:Plasmin and matrix metalloproteinases in vascular remodeling. 1148 21

Plasminogen activator (PA) inhibitor-1 (PAI-1) has been recognized as a surrogate marker of endothelial dysfunction in diseases associated with impaired angiogenesis, including atherosclerosis, diabetic vasculopathy, and nephropathy. To establish the necessary and sufficient components of the PA system [PAI-1, urokinase-type PA (uPA), or tissue-type PA (tPA), and plasminogen (Plg)] for angiogenesis, we examined angiogenic competence of vascular explant cultures obtained from mice deficient in PAI-1, tPA, uPA, and Plg. To gain insight into the requirement for different matrix-degrading systems during endothelial cell migration across plasmin-degradable basement membranes compared with profibrotic areas containing plasmin-nondegradable collagen, we contrasted vascular sprouting in collagen with Matrigel lattices. PAI-1(-/-) vessels showed an increased capillary sprouting in both collagen and Matrigel. Deficiency of uPA significantly reduced the rate of sprouting, whereas tPA(-/-) vessels showed a profound inhibition of capillary sprouting. The Plg(-/-) vessels failed to sprout, a defect that was restored not only by exogenous Plg, but also by the addition of PAs; a nonproteolytic effect of tPA was observed in Matrigel. Zymography revealed no differences in the activity of metalloproteinase (MMP)-2 and -9 in wild-type and PAI-1(-/-) vessels, but demonstrated reduced MMP-9 activity in all angiogenesis-deficient vessels. In summary, 1) PAI-1 by itself is a modest inhibitor of endothelial sprouting, 2) tPA and Plg are indispensable for angiogenesis in this model, 3) Plg is not the only substrate for PAs, and 4) the activity of MMP-9 is undetectable in explant cultures from tPA and Plg knockout mice.
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PMID:Plasmin-dependent and -independent effects of plasminogen activators and inhibitor-1 on ex vivo angiogenesis. 1155 72

Calcification of elastin occurs in many pathological cardiovascular diseases including atherosclerosis. We have previously shown that purified elastin when subdermally implanted in rats undergoes severe calcification and aluminum chloride (AlCl(3)) pretreatment of elastin inhibits calcification. In the present study we investigated whether matrix metalloproteinase (MMP) binding to elastin and elastin degradation is prevented by AlCl(3) pretreatment. Subdermal implantation of AlCl(3)-pretreated elastin showed significantly lower MMP-9 and MMP-2 activity surrounding the implant as compared to the control implants. AlCl(3) pretreatment also significantly inhibited elastin implant calcification at the seven-day implant period (AlCl(3)-pretreated 4.07 +/- 1.27, control 23.82 +/- 2.24 microg/mg; p<0.0001). Moreover, elastin gel zymography studies showed that gel pretreatment with AlCl(3) inhibited elastolysis by MMP-9. We also demonstrate significant suppression of MMP-2 activity in aortic wall segments of AlCl(3)-pretreated porcine bioprosthetic heart valve implants as compared to control valve implants in sheep mitral valve replacement studies. AlCl(3) pretreatment also significantly inhibited calcification of elastin in this model. Thus, we conclude that aluminum ion binding to elastin prevents MMP-mediated elastolysis and thus prevents elastin calcification.
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PMID:Aluminum chloride pretreatment of elastin inhibits elastolysis by matrix metalloproteinases and leads to inhibition of elastin-oriented calcification. 1173 47

Tumor necrosis factor (TNF) receptor superfamily 14 (TNFRSF14) is the cellular receptor for TNF superfamily 14 (LIGHT). Immunohistochemical staining of human carotid atherosclerotic plaques revealed a high level of expression of the TNFRSF14 in regions rich in macrophages/foam cells. To investigate the role of TNFRSF14 in the functioning of monocytes in relation to atherogenesis, we have analyzed TNFRSF14 expression levels and cellular events after stimulation of TNFRSF14 in peripheral blood monocytes or the human macrophage-like cell line, THP-1. A high level of expression of TNFRSF14 was detected in activated monocytes, in macrophages derived from monocytes, and in THP-1 cells. Concomitant activation of THP-1 cells with interferon-gamma and immobilized anti-TNFRSF14 monoclonal antibody resulted in synergistic induction of proatherogenic cytokines, such as TNF-alpha and interleukin-8. Activation of THP-1 cells with immobilized anti-TNFRSF14 monoclonal antibody induced expression of matrix metalloproteinase (MMP)-1, MMP-9, MMP-13, and tissue inhibitors of metalloproteinase-1 and -2. Furthermore, immunohistochemical staining of atherosclerotic plaques with severe infiltration of foam cells revealed that the expression patterns of TNFRSF14 and MMP-1, -9, and -13 overlapped. Treatment of THP-1 cells with soluble LIGHT also caused induction of MMP-9 and interleukin-8. These data suggest that TNFRSF14 is involved in atherosclerosis via the induction of proatherogenic cytokines and decreasing plaque stability by inducing extracellular matrix-degrading enzymes.
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PMID:Tumor necrosis factor receptor superfamily 14 is involved in atherogenesis by inducing proinflammatory cytokines and matrix metalloproteinases. 1174 58

The tetracyclines function as antibiotics by inhibiting bacterial protein synthesis, but recent work has shown that they are pluripotent drugs that affect many mammalian cell functions including proliferation, migration, apoptosis, and matrix remodeling. Because all of these processes have been implicated in arterial intimal lesion development, the objective of these studies was to examine the effect of doxycycline treatment using a well-characterized model of neointimal thickening, balloon catheter denudation of the rat carotid artery. Rats were treated with 30-mg/kg/day doxycycline. Doxycycline reduced the activity of matrix metalloproteinase (MMP)-2 and MMP-9 in the arterial wall, and inhibited smooth muscle cell migration from media to intima by 77% at 4 days after balloon injury. Replication of smooth muscle cells in the intima at 7 days was reduced from 28.3 plus minus 2.5% in controls to 17.0 +/- 2.8% in doxycycline-treated rats. The synthesis of elastin and collagen was not affected, but accumulation of elastin was blocked in the doxycycline-treated rats. By contrast, collagen accumulation was not affected, which led to the formation of a more collagen-rich intima. At 28 days after injury, the intimal:medial ratio was significantly reduced from 1.67 +/- 0.09 in control rats to 1.36 +/- 0.06 in the doxycycline-treated rats. This study shows that doxycycline is an effective inhibitor of cell proliferation, migration, and MMP activity in vivo. Further study in more complicated models of atherosclerosis and restenosis is warranted.
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PMID:Doxycycline modulates smooth muscle cell growth, migration, and matrix remodeling after arterial injury. 1189 Dec 5

Several matrix metalloproteinases (MMPs), including MMP-1, -3, and -9, mediate matrix destruction during chronic inflammatory diseases such as arthritis and atherosclerosis. MMP up-regulation by inflammatory cytokines involves interactions between several transcription factors, including activator protein-1 and nuclear factor kappaB (NF-kappaB). The upstream regulatory pathways are less well understood. We investigated the role of isoforms of protein kinase C (PKC) in basic fibroblast growth factor- and interleukin-1alpha-mediated MMP production from cultured rabbit aortic smooth muscle cells. A synthetic PKC inhibitor, RO318220, inhibited MMP-1, -3, and -9 production by 89 +/- 3, 75 +/- 18, and 89 +/- 9%, respectively. However, down-regulation of conventional and novel isoforms did not inhibit but rather increased MMP-9 production by 48 +/- 16%, implicating an atypical PKC isoform. Consistent with this, PKCzeta protein levels and activity were stimulated 3.3- and 13-fold, respectively, by basic fibroblast growth factor plus interleukin-1alpha and antisense oligonucleotides to PKCzeta significantly decreased MMP-9 formation by 62 +/- 18% compared with scrambled sequences. Moreover, adenovirus-mediated overexpression of a dominant-negative (DN) PKCzeta reduced MMP-1, -3, and -9 production by 78 +/- 9, 76 +/- 8, and 76 +/- 5%, respectively. DN-PKCzeta inhibited NF-kappaB DNA binding but did not affect ERK1/2 activation or AP-1 binding. Antisense PKCzeta oligonucleotides and DN-PKCzeta stimulated cell proliferation by 89 +/- 14% (n = 4) and 305 +/- 74% (n = 3), respectively (both p < 0.05). Our results show that PKCzeta is essential for cytokine-induced up-regulation of MMP-1, -3, and -9, most likely by activating NF-kappaB. Selective inhibition of PKCzeta is therefore a possible strategy to inhibit MMP production in inflammatory diseases such as atherosclerosis.
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PMID:Activation of protein kinase Czeta is essential for cytokine-induced metalloproteinase-1, -3, and -9 secretion from rabbit smooth muscle cells and inhibits proliferation. 1200 Jul 46

Saphenous vein (SV) grafts are commonly used to bypass coronary arteries that are diseased due to atherosclerosis. However, the development of intimal hyperplasia in such grafts can lead to patency-threatening stenosis and re-occlusion of the vessel. The proliferation and migration of smooth muscle cells (SMC) play key roles in the development of intimal hyperplasia, and an agent that inhibits both of these processes therefore has therapeutic potential. A prerequisite for SMC proliferation and migration in vivo is degradation of the basement membrane, achieved by secretion of the matrix-degrading gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9. Statins are cholesterol-lowering drugs that also have direct effects on SMC function. Here we report that neointima formation in organ-cultured human SV segments is inhibited by simvastatin, an effect that is associated with reduced MMP-9 activity. Additionally, our work shows that simvastatin not only inhibits proliferation, but importantly also inhibits invasion (migration through a matrix barrier), of cultured human SV SMC. Thus simvastatin treatment appears to inhibit neointima formation as a result of combined inhibition of SMC proliferation and invasion. The potential intracellular mechanisms by which statins affect SMC proliferation and migration, and thus attenuate intimal hyperplasia, are discussed, with particular emphasis on the role of MMP-9.
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PMID:Statins for the prevention of vein graft stenosis: a role for inhibition of matrix metalloproteinase-9. 1202 38

The clinical efficacy and safety of pitavastatin (NK-104), a novel HMG-CoA reductase inhibitor, during long-term treatment, were examined in 25 patients (male/female=11/14, mean age=53+/-13 (mean+/-SD) years) with heterozygous familial hypercholesterolemia (FH). After a period on placebo of >4 weeks, 2 mg/day of pitavastatin was administered for 8 weeks, and the dose was increased to 4 mg/day for up to 104 weeks. Total cholesterol (TC) decreased by 31% from the initial value of 340+/-57 to 237+/-40 mg/dl (P<0.0001) at week 8. During treatment with the higher dose, TC decreased even further to 212+/-35 mg/dl at week 12; it decreased by 37% from the initial value (P<0.0001). Similarly, the baseline low-density lipoprotein (LDL)-cholesterol (LDL-C) decreased by 41% at week 8, and by 49% at week 12, from 267+/-61 mg/dl at baseline. These findings indicate a dose-dependent effect of the drug on TC and LDL-C concentrations. To examine whether the levels of circulating matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases: TIMPs) are altered during lipid-lowering therapy, we also measured their plasma levels. The mean levels of MMP-2 and -3 were significantly increased. No significant alteration was found in MMP-9, TIMP-1 and -2 levels. As for the safety of pitavastatin, adverse reactions were observed in one case (4%) of subjective and objective symptoms. The effects of pitavastatin on TC and LDL-C were stable during long treatment of patients with heterozygous FH.
Atherosclerosis 2002 Jul
PMID:Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients with heterozygous familial hypercholesterolemia. 1204 34


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