A C Newby

..Nitric oxide synthase, prostacyclin synthase, and tissue inhibitors of metalloproteinases have been used to reduce neointima formation, and vein graft atheroma remains a challenge for the future...

..We conclude that MMPs influence VSMC behaviour by cleaving both matrix and non-matrix substrates...

..Impaired cap formation caused by smooth muscle senescence, mummification and propensity to apoptosis may be as important as increased cap destruction in promoting plaque rupture...

..Inhibiting the activity of specific MMPs or preventing their upregulation could ameliorate intimal thickening and prevent myocardial infarction...

..Evidence is reviewed from genetically modified mice and human biomarker and genetic studies that sheds light on this dual role of metalloproteinases...

..Moreover, recent evidence suggests that different macrophage phenotypes express characteristically different spectra of MMPs and their inhibitors. New therapies may result from targeting matrix MMP overproduction...

..Given the dual effects of MMPs, therapies should selectively target harmful MMPs or the processes that cause MMP activity to rise to destructive levels...

..These phenotypes could play differing roles in cap, core and aneurysm formation...

..These findings have important implications for the physiological roles of TIMPs and their use in gene therapy...

..Here, we overexpressed TIMP-3 at the luminal surface of human saphenous veins before organ culture and in pig saphenous veins before interposition grafting into carotid arteries in vivo to assess neointima formation...

..Moreover, an NF-kappaB binding site is present in the promoter of the MMP-9 gene and an NF-kappaB-like element in the promoter of the MMP-1 gene...

..MMPs therefore constitute new therapeutic targets for reducing late vein graft failure...

....

..In summary, atherosclerosis increases TIMP expression, which counterbalances, in part, increased MMP activity...

..It emphasizes the key roles played by growth factors and extracellular matrix-degrading metalloproteinases, which act in concert to remodel the extracellular matrix and permit cell migration and proliferation...

..It will also consider the implications for the consequences and early detection of vascular drug toxicity...

....

..The effect of the NO donor, NONOate and iloprost on O(2)(-) formation, p47(phox) and Rac(1) activation in human vascular smooth muscle cells (hVSMCs) was investigated...

..In conclusion, elements from the LOX-1 promoter and Tie2 enhancer together with an intron can be used to improve vectors for vascular gene transfer...

..Our data imply the existence of at least two genes for cN-I, cN-I(A), previously cloned from pigeon and human, and cN-I(B) that we report here from mouse and partially from human...

..These results show that TIMP-3 inhibits invasion in vitro and promotes apoptosis in cancer cell type of differing origin. This clearly identifies the potential of TIMP-3 for gene therapy of multiple cancer types...

..This study establishes that macro-porosity is one essential feature required to reduce PDGF expression cell proliferation and neointima formation...

..To determine whether there is an association between vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac(1) and PDE type 5 (PDE5) in human vascular smooth muscle cell (hVSMCs)...

..Our results imply distinct roles for cN-I and cN-II. Under the conditions tested in these cells, only cN-I plays a significant role in AMP breakdown to adenosine, whereas only cN-II breaks down IMP to inosine and GMP to guanosine...

....

..DN.Akt) or an Akt-resistant Foxo-3a (Ad.AAA-Foxo-3a). These results newly demonstrate the cardiac prosurvival action of NGF and provide mechanistic information on the signaling pathway, which encompasses trkA, PI3K-Akt, and Foxo...

..Statins did not affect MMP mRNA levels. CONCLUSIONS: Statins inhibit secretion of a several MMPs from both SMCs and macrophages, which could therefore contribute to their plaque-stabilizing effects...

..These data demonstrate for the first time that Skp2 is an important factor in VSMC proliferation and its inhibition by cyclic nucleotides...

..We hypothesized that overexpression of tissue inhibitor of metalloproteinase (TIMP)-1 or TIMP-2 would attenuate atherosclerotic plaque development and instability in high fat-fed apolipoprotein E-knockout (apoE(-/-)) mice...

..We investigated short- and long-term effects of anti-proliferative pharmacological agents on experimental pig vein-grafts with similar dimensions and kinetics to human coronary grafts...

....

..Because the inhibition of NF-kappaB reduces proteolytic activity, it appears to be an attractive pharmacological target in unstable atheromas...

..We sought to identify genes differentially regulated in foam cells, since these are likely to include new targets for intervention...

..Selective inhibition of PKCzeta is therefore a possible strategy to inhibit MMP production in inflammatory diseases such as atherosclerosis...

..To find an effective means for delivering therapeutic genes of Tissue inhibitor of metalloproteinase-3 (TIMP-3) to the target sites of the dilated coronary artery for the purpose of preventing restenosis of the injured artery...

..Taken together, these results indicate that TIMP-3 overexpression induces a type II apoptotic pathway initiated via a Fas-associated death domain-dependent mechanism...

....

..An excess of metalloproteinases (MMPs) over tissue inhibitors of metalloproteinases (TIMPs) may favor atherosclerotic plaque rupture. We compared TIMP levels in nonfoamy and foam-cell macrophages (FCM) generated in vivo...

..The mechanism of cell death was apoptosis. CONCLUSION: The previously unreported finding of TIMP-3 induced apoptosis of RPE cells may account for some of the early features seen in SFD and ARMD...

..CONCLUSIONS: Cell cycle entry is prevented in aortic tissue, and this is associated with an inability to downregulate p16 and p27 CKIs, and therefore to activate cyclin D1 and cyclin E associated kinase activities...

..Our results imply that only normal levels of 6-O-sulfation maintained by sulf1 are optimal for several functions of VSMC...

..Outside-in signaling from the cadherin:beta-catenin complex can increase transcription of the cell-cycle gene cyclin D1; however, its role in VSMC proliferation has only recently been considered...

..This might be enough by itself to decrease later atherosclerosis. Alternatively, direct targeting with nitric oxide synthase, decoy adhesion molecules, or interleukin-10 might be possible...

..Studying the detailed mechanisms involved may suggest possibilities for intervening selectively against pathological MMP induction...

..005). CONCLUSIONS: Our results demonstrate for the first time to our knowledge the feasibility of adenovirus-coated stent technology and highlight the potential of TIMP-3 to produce significant inhibition of in-stent neointima formation...

..Furthermore, disruption of N-cadherin cell-cell contacts mediated in part by metalloproteinase activity occurs during VSMC proliferation, releasing beta-catenin and possibly inducing beta-catenin-mediated intracellular signaling...

..Here we investigate the mechanisms regulating p21Cip1 levels in VSMCs and its role in controlling VSMC proliferation...

..These data demonstrate that MMPs are directly involved in atherosclerotic plaque destabilization and clearly show that members of the MMP family have widely differing effects on atherogenesis...

....

..Taken together, these data demonstrate that the vascular ECM controls SMC proliferation via FAK-dependent regulation of Skp-2 protein stability...

..90 +/- 4 beats/min). Our results demonstrate that overexpressed cN-IA can be sufficiently active in cardiomyocytes to generate physiologically effective concentrations of adenosine at its receptors...

..We have demonstrated for the first time the potential for third-generation lentiviral vectors, but not alternate AAV serotypes, as efficient vascular gene delivery vectors...

..This identifies the CD40-TRAF6 axis as a potential therapeutic target in vascular disease...

..These mechanisms could promote matrix turnover in inflammatory states and, for example, promote atherosclerotic plaque rupture...

..Therefore, a further mechanism featuring gap junction-mediated communication may be implicated in immune regulation...

..These results define a novel role for PKCzeta as a shared signaling mediator for flow and TNF-alpha, and important for flow-mediated inhibition of proinflammatory and apoptotic events in ECs...

..Sorsby's fundus dystrophy (SFD) is a degenerative retinopathy characterised by accumulation of mutant TIMP-3 protein in Bruch's membrane...

..Adenovirus-mediated overexpression of the Gly-167 mutant also caused RPE apoptosis dose-dependently. Apoptosis of RPE cells might therefore contribute to the pathology of SFD...

..These experiments imply that either integrin might be targeted to reduce monocyte infiltration into HSV grafts...

....