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

Lysophosphatidylcholine (lysoPC) is implicated in the development of atherosclerosis and certain autoimmune diseases, and is reported to induce tissue-type plasminogen activator (tPA) at the protein level in endothelial cells. This study was designed to investigate the effect of lysoPC on tPA gene expression and the underlying molecular mechanisms in cultured endothelial cells. LysoPC transiently induced the mRNA expression of tPA in endothelial cells. LysoPC also induced the mRNA expression of urokinase-type plasminogen activator (uPA), uPA receptor, and plasminogen activator inhibitor-1, but the kinetics were different from that of tPA. Promoter analysis revealed that the cyclic AMP-responsive element of the tPA gene (tPACRE) is required for lysoPC-induced tPA expression. Furthermore, an electrophoresis mobility shift assay showed that lysoPC increased the binding activity of CRE binding protein to tPACRE. These results indicated that lysoPC transcriptionally upregulated the gene expression of tPA in endothelial cells, at least in part, via tPACRE activation.
 ...
PMID:Lysophosphatidylcholine induces tPA gene expression through CRE-dependent mechanism. 1572 Dec 75

Chlamydia (C.) pneumoniae are thought to infect monocytes and use them as vectors into the vessel wall, where they may accelerate atherosclerosis. We investigated the effects of C. pneumoniae on monocytic matrix metalloproteinase (MMP) activation with focus on the role of the extracellular matrix metalloproteinase inducer EMMPRIN. Human monocytes or monocytic MonoMac6 cells were infected with C. pneumoniae. Infection enhanced mRNA- and surface expression of EMMPRIN and Membrane-type-1 Matrix Metalloproteinase (MT1-MMP), plus the secretion of MMP-7, MMP-9 and the urokinase receptor (uPAR). Chlamydial heat shock protein 60 was identified to be partially responsible for EMMPRIN and MMP-9 induction, while C. trachomatis-infection had no stimulatory effect, indicating a C. pneumoniae-specific activation pathway. Suppression of EMMPRIN by gene silencing almost completely hindered the induction of MT1-MMP and MMP-9 by C. pneumoniae, suggesting a predominant regulatory role for EMMPRIN. Moreover, C. pneumoniae-infected monocytes exhibited increased MMP- and plasmin-dependent migration through "matrigel". Additionally, incubation of SMCs with supernatants of C. pneumoniae-infected monocytes induced MMP-2 activation, which was inhibited by IL1-Receptor antagonist or anti-IL-6-mAb, indicating paracrine intercellular activation pathways. In conclusion, C.pneumoniae induce MMP activity directly in monocytes through an EMMPRIN-dependent pathway and indirectly in SMCs via monocyte-derived cytokines.
 ...
PMID:EMMPRIN (CD 147) is a central activator of extracellular matrix degradation by Chlamydia pneumoniae-infected monocytes. Implications for plaque rupture. 1654 74

Vascular diseases, such as atherosclerosis, thromboembolic disorders and stroke, in addition to surgical procedures such as restenosis, all share the plasminogen activator system as a central component in the pathogenesis of vascular injury. Since the development of plasminogen deficient mice our knowledge of the effects of this proteolytic system in cardiovascular disease has vastly increased. The plasminogen activator system plays a key role in vascular homeostasis and constitutes a critical response mechanism to cardiovascular injury. The central components of the PA system are the proteolytic activators, urokinase-plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA), plasminogen (plg) and its degradation product, plasmin, together with the major inhibitors of this system, plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2). An extensive network of additional proteases, inhibitors, receptors and modulators directly associate and are influenced by the PA system, the largest group being the Matrix Metalloproteinases (MMPs) and their respective inhibitors the Tissue inhibitors of MMPs (TIMPS).
 ...
PMID:Plasminogen activator system and vascular disease. 1661 Nov 53

Clinical as well as experimental evidence suggests that vascular overexpression of plasminogen activator inhibitor (PAI)-1, the primary physiological inhibitor of both urokinase and tissue-type plasminogen activator, may be involved in the pathophysiology of atherosclerosis and cardiovascular disease. We investigated the feasibility, efficacy and functional effects of PAI-1 gene silencing in human vascular endothelial cells using small interfering RNA. Double-stranded 21 bp-RNA molecules targeted at sequences within the human PAI-1 gene were constructed. Successful siRNA transfection of HUVEC was confirmed using fluorescence microscopy and flow cytometry. One of five candidate siRNA sequences reduced PAI-1 mRNA and protein in a concentration- and time-dependent manner. Suppression of PAI-1 mRNA was detected up to 72 hours after transfection. Moreover, siRNA treatment reduced the activity of PAI-1 released from HUVEC, and prevented the oxLDL- or LPS-induced upregulation of PAI-1 secretion. Importantly, siRNA treatment did not affect the expression of other endothelial-cell markers. Moreover, downregulation of PAI-1 significantly enhanced the ability of endothelial cells to adhere to vitronectin, and this effect could be reversed upon addition of recombinant PAI-1. SiRNA-mediated reduction of PAI-1 expression may be a promising strategy for dissecting the effects of PAI-1 on vascular homeostasis.
 ...
PMID:Successful silencing of plasminogen activator inhibitor-1 in human vascular endothelial cells using small interfering RNA. 1667 78

Nattokinase has been reported as an oral health product for the prevention of atherosclerosis. We developed a novel strategy to express a nattokinase from Bacillus subtilis in a live delivery vehicle, Lactococcus lactis. Promoter P( nisZ) and signal peptide SP(Usp) were used for inducible and secretory expression of nattokinase in L. lactis. Western blotting analysis demonstrated that nattokinase was successfully expressed, and about 94% of the enzyme was secreted to the culture. The recombinant nattokinase showed potent fibrinolytic activity, equivalent to 41.7 urokinase units per milliliter culture. Expression and delivery of such a fibrinolytic enzyme in the food-grade vehicle L. lactis would facilitate the widespread application of nattokinase in the control and prevention of thrombosis diseases.
 ...
PMID:Secretory expression of a heterologous nattokinase in Lactococcus lactis. 1722 95

The urokinase (uPA)/urokinase receptor (uPAR) multifunctional system is an important mediator of migration and proliferation of vascular smooth muscle cells (VSMC). However, whether uPA/uPAR-directed mechanisms are involved in the beneficial effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on vascular remodeling remains unexplored. In this study, we have investigated the effect of the hydrophilic statin rosuvastatin on neointimal remodeling, and the role of uPAR. Using an ex vivo organ and in vitro cell culture models we demonstrate that rosuvastatin decreases injury-induced neointima formation and proliferation of medial VSMC in porcine coronary arteries, as well as migration and proliferation of human coronary VSMC. Studies on the underlying mechanisms show that rosuvastatin impairs VSMC transition from their physiological contractile to the pathophysiological synthetic phenotype. These effects are mediated, at least in part, via uPAR, as confirmed by means of rosuvastatin-directed uPAR expression and uPAR silencing in both models. Our findings provide evidence that rosuvastatin modulates VSMC phenotypic changes and subsequently their proliferation and migration, and indicate the important role for uPAR in these processes. This mechanism contributes to the beneficial non-lipid lowering effect of rosuvastatin on negative vascular remodeling.
Atherosclerosis 2007 Dec
PMID:Rosuvastatin regulates vascular smooth muscle cell phenotypic modulation in vascular remodeling: role for the urokinase receptor. 1727 28

The urokinase-type plasminogen activator (uPA), its inhibitor PAI-1 and its cellular receptor (uPAR), play a pivotal role in pericellular proteolysis. In addition, through their interactions with extracellular matrix proteins as well as with transmembrane receptors and other links to the intracellular signaling machinery, they modulate cell migration, cell-matrix interactions and signaling pathways. A large body of experimental evidence from in-vitro and in-vivo data as well as from the clinics indicates an important role of the uPA-uPAR-PAI-1 systems in cancer. In addition to their role in tumor cell biology, the uPA-uPAR-PAI-1 systems are also important for vascular biology by modulating angiogenesis and by altering migration of smooth muscle cells and fibrin deposition in atherosclerosis and restenosis. This review will focus on the general mechanism of uPAR/uPA/PAI-1 interactions and signaling and the possible relevance of this system in vascular biology.
 ...
PMID:uPAR-uPA-PAI-1 interactions and signaling: a vascular biologist's view. 1733 98

The regulation of plasmin generation on cell surfaces is of critical importance in the control of vascular homeostasis. Cell-derived microparticles participate in the dissemination of biological activities. However, their capacity to promote plasmin generation has not been documented. In this study, we show that endothelial microparticles (EMPs) from tumor necrosis factor alpha (TNFalpha)-stimulated endothelial cells served as a surface for the generation of plasmin. The generation of plasmin involved expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) at the surface of EMPs and was further increased by their ability to bind exogenous uPA on uPAR. Plasminogen was activated at the surface of EMPs in a dose-dependent, saturable, and specific manner as indicated by the inhibition of plasmin formation by epsilon-amino-caproic acid (epsilon-ACA) and carboxypeptidase B. EMP-induced plasmin generation affects tube formation mediated by endothelial progenitor cells. However, low amounts of EMPs increased tube formation, whereas higher concentrations inhibited it. Prevention of these effects by inhibitors of either uPA or plasmin underscore the key role of EMP-induced plasmin generation. In conclusion, we demonstrated that EMPs act as vectors supporting efficient plasmin generation and dissemination, a new pathway in the regulation of endothelial proteolytic activities with potential involvement in inflammation, angiogenesis, and atherosclerosis.
 ...
PMID:Activation of plasminogen into plasmin at the surface of endothelial microparticles: a mechanism that modulates angiogenic properties of endothelial progenitor cells in vitro. 1760 60

During recent years it has become evident that atherosclerosis is an inflammatory disease. Furthermore, immune reactions and especially autoimmunity, were demonstrated to modulate atherosclerosis in animal experiments. An interesting example of how autoimmune reactions can influence atherosclerosis and consequences thereafter, is systemic lupus erythematosus (SLE)-associated cardiovascular disease (CVD). Antithrombotic effect exerted by Annexin A5 (ANXA5) is thought to be mediated mainly by forming a mechanical shield over phospholipids (PLs) reducing availability of PLs for coagulation reactions. However, more specific properties of ANXA5 might be of importance for its antithrombotic function. Such examples include downregulation of surface-expressed tissue factor (TF), as well as upregulation of urokinase-type plasminogen activator (uPA) by ANXA5. Also, interaction of ANXA5 with ligands involved in hemostasis, such as sulfatide and heparin, has been demonstrated. We have recently described a novel mechanism potentially contributing to atherothrombosis in SLE, with ANXA5 binding to endothelium decreased in SLE, an effect caused by antiphospholipid antibodies (aPL). It may be hypothesized that ANXA5 can be effective as a treatment to prevent plaque rupture and atherothrombosis not only in SLE, but also in the general population prone to CVD. Antiatherothrombotic potential of ANXA5 deserves further attention and careful studies as the mechanism behind the majority of clinically significant cardiovascular ischemic disease is atherothrombosis, formed on an underlying vulnerable atherosclerotic lesion. It may be hypothesized that ANXA5 can be effective as a treatment to prevent plaque rupture and atherothrombosis not only in SLE, but also in a general population prone to CVD.
 ...
PMID:Annexin A5 as a novel player in prevention of atherothrombosis in SLE and in the general population. 1789 75

The endothelium plays a key role in the development of atherogenesis and its inflammatory and proliferative status influences the progression of atherosclerosis. The aim of this study is to compare the effects of two beta blockers such as nebivolol and atenolol on gene expression in human umbilical vein endothelial cells (HUVECs) following an oxidant stimulus. HUVECs were incubated with nebivolol or atenolol (10 micromol/L) for 24 hours and oxidative stress was induced by the addition of oxidized (ox)-LDL. Ox-LDL upregulated adhesion molecules (ICAM-1, ICAM-2, ICAM-3, E-selectin, and P-selectin); proteins linked to inflammation (IL-6 and TNFalpha), thrombotic state (tissue factor, PAI-1 and uPA), hypertension such as endothelin-1 (ET-1), and vascular remodeling such as metalloproteinases (MMP-2, MMP-9) and protease inhibitor (TIMP-1). The exposure of HUVECs to nebivolol, but not to atenolol, reduced these genes upregulated by oxidative stress both in terms of protein and RNA expression. The known antioxidant properties of the third generation beta blocker nebivolol seem to account to the observed differences seen when compared to atenolol and support the specific potential protective role of this beta blocker on the expression of a number of genes involved in the initiation and progression of atherosclerosis.
 ...
PMID:Effects of nebivolol on endothelial gene expression during oxidative stress in human umbilical vein endothelial cells. 1843 28


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>