UMLS:C0004153 - FACTA Search

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 chemotactic protein-1 (MCP-1), a potent chemoattractant for monocytes, is thought to play a major role in atherosclerosis, but whether its atherogenic effects involve the direct modulation of vascular smooth muscle cell (SMC) functions remains unclear. This study examined the effects of MCP-1 on the migration of cultured A7r5 SMCs and the signaling pathways involved. Addition of recombinant MCP-1 stimulated SMC migration in modified Boyden chambers coated with type I collagen in a concentration-dependent manner, with 10(-9) M being maximally effective. Using untreated A7r5 cells, two MCP-1 receptors, CCR2 and CCR4, were detected and MCP-1 secretion was significantly increased by stimulation with platelet-derived growth factor. MCP-1-stimulated A7r5 migration was completely blocked by the NAD(P)H oxidase inhibitor, diphenylene iodonium (DPI), and dose-dependently inhibited by polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), suggesting a role for reactive oxygen species (ROS) in this process. During MCP-1 stimulation, ROS production increased rapidly, then gradually decayed over 60 min, and this effect was markedly decreased by pretreatment with DPI or PEG-SOD. Interestingly, U0126 and PD98059, which inhibit activation of extracellular signal-regulated kinases 1/2 (ERK 1/2), significantly inhibited MCP-1-activated ROS generation. Furthermore, transfection of an active mutant of MEK1 (ERK 1/2 kinase) markedly increased superoxide production in rat aortic smooth muscle cells, as detected by dihydroethydium staining, suggesting that ERK 1/2 activation stimulates ROS generation. ERK 1/2 activation was increased for at least 30 min in cells incubated with MCP-1, and this effect was abolished by U0126 or DPI pretreatment. These results demonstrate that MCP-1 is a chemoattractant for SMCs and that MCP-1-stimulated migration requires both ROS production and ERK 1/2 activation in a positive activation loop, which may contribute to the atherogenic effects of MCP-1.
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PMID:Reactive oxygen species and ERK 1/2 mediate monocyte chemotactic protein-1-stimulated smooth muscle cell migration. 1591 91

Nanoscale particles could be synthetically designed to potentially intervene in lipoprotein matrix retention and lipoprotein uptake in cells, processes central to atherosclerosis. We recently reported on lipoprotein interactions of nanoscale micelles self-assembled from amphiphilic scorpion-like macromolecules based on a lauryl chloride-mucic acid hydrophobic backbone and poly(ethylene glycol) shell. These micelles can be engineered to present varying levels of anionic chemistry, a key mechanism to induce differential retentivity of low-density lipoproteins (LDL) (Chnari, E.; Lari, H. B.; Tian, L.; Uhrich, K. E.; Moghe, P. V. Biomaterials 2005, 26, 3749). In this study, we examined the cellular interactions and the ability of carboxylate-terminated nanoparticles to modulate cellular uptake of differentially oxidized LDL. The nanoparticles were found to be highly biocompatible with cultured IC21 macrophages at all concentrations examined. When the nanoparticles as well as LDL were incubated with the cells over 24 h, a marked reduction in cellular uptake of LDL was observed in a nanoparticle concentration-dependent manner. Intermediate concentrations of nanoparticles (10(-6) M) elicited the most charge-specific reduction in uptake, as indicated by the difference in uptake due to anionic and uncharged nanoparticles. At these concentrations, anionic nanoparticles reduced LDL uptake for all degrees of oxidation (no oxidation, mild, high) of LDL, albeit with qualitative differences in the effects. The anionic nanoparticles were particularly effective at reducing the very high levels of uptake of the most oxidized level of LDL. Since complexation of LDL with anionic nanoparticles is reduced at higher degrees of LDL oxidation, our results suggest that anionic nanoparticles interfere in highly oxidized (hox) LDL uptake, likely by targeting cellular/receptor uptake mechanism, but control unoxidized LDL uptake by mechanisms related to direct LDL-nanoparticle complexation. Thus, anionically functionalized nanoparticles can modulate the otherwise unregulated internalization of differentially oxidized LDL.
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PMID:Nanoscale anionic macromolecules can inhibit cellular uptake of differentially oxidized LDL. 1647 36

Flow-induced dilation (FID) is an important physiological stimulus that regulates tissue blood flow and is mediated by endothelium-derived factors that play a role in vascular integrity and the development of atherosclerosis. In coronary artery disease (CAD), conduit artery FID is impaired. The purpose of this study was to determine the mechanism of FID in human visceral adipose and examine whether the presence of conduit coronary atherosclerosis is associated with altered endothelial function in visceral fat. FID was determined in isolated visceral fat arterioles from patients with and without CAD. After constriction with endothelin-1, increases in flow produced an endothelium-dependent vasodilation that was sensitive to N(omega)-nitro-l-arginine methyl ester (l-NAME) in visceral fat arterioles from patients without CAD. In contrast, l-NAME alone or in combination with indomethacin had no effect on FID in similarly located arterioles from patients with CAD. Flow increased dichlorofluorescein (DCF) and dihydroethidium fluorescence accumulation in arterioles from patients with CAD versus without, indicative of the production of oxidative metabolites and superoxide, respectively. Both the dilation and DCF fluorescence to flow were reduced in the presence of the H(2)O(2) scavenger polyethylene glycol-catalase. Exogenous H(2)O(2) elicited similar relaxations of arterioles from patients in both groups. These data indicate that FID in visceral fat arterioles is nitric oxide dependent in the absence of known CAD. However, in the presence of CAD, H(2)O(2) replaces nitric oxide as the mediator of endothelium-dependent FID. This study provides evidence that adverse microvascular changes during CAD are evident in human visceral adipose, a tissue associated with CAD.
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PMID:The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD. 1704 Sep 67

The purpose of this study was to evaluate Fullerene as a therapeutic photosensitizer in the treatment of atherosclerosis. An atherosclerotic experimental rabbit model was prepared by causing intimal injury to bilateral external iliac arteries using balloon expansion. In four atherosclerotic rabbits and one normal rabbit, polyethylene glycol-modified Fullerene (Fullerene-PEG) was infused into the left external iliac artery and illuminated by light emitting diode (LED), while the right external iliac artery was only illuminated by LED. Two weeks later, the histological findings for each iliac artery were evaluated quantitatively and comparisons were made among atherosclerotic Fullerene+LED artery (n = 4), atherosclerotic light artery (n = 4), normal Fullerene+LED artery (n = 1), and normal light artery (n = 1). An additional two atherosclerotic rabbits were studied by fluorescence microscopy, after Fullerene-PEG-Cy5 complex infusion into the left external iliac artery, for evaluation of Fullerene-PEG incorporated within the atherosclerotic lesions. The degree of atherosclerosis in the atherosclerotic Fullerene+LED artery was significantly (p < 0.05) more severe than that in the atherosclerotic LED artery. No pathological change was observed in normal Fullerene+LED and LED arteries. In addition, strong accumulation of Fullerene-PEG-Cy5 complex within the plaque of the left iliac artery of the two rabbits was demonstrated, in contrast to no accumulation in the right iliac artery. We conclude that infusion of a high concentration of Fullerene-PEG followed by photo-illumination resulted not in a suppression of atherosclerosis but in a progression of atherosclerosis in experimental rabbit models. However, this intervention showed no adverse effects on the normal iliac artery.
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PMID:Is the use of fullerene in photodynamic therapy effective for atherosclerosis? 1804 Jul 38

The increased expression of VCAM-1 on endothelial segments within plaque regions could be used as a target to deliver polymeric drug carriers selectively to sites of atherosclerosis. We probed the hypothesis that polymeric particles conjugated with a ligand for VCAM-1 exhibit selective and avid adhesion to sites of atherosclerosis. Particles made from polystyrene or the biodegradable polymer poly(sebacic acid)-block-polyethylene glycol (PSA-PEG) were conjugated with an antibody to VCAM-1 (alpha-VCAM-1) or IgG (negative control). The particles were injected into the jugular vein of ApoE(-/-) (a murine model of atherosclerosis) or wild type mice and their adhesion to the aorta determined. alpha-VCAM-1 particles exhibited significantly greater adhesion to ApoE(-/-) mouse aorta [32 +/- 5 (mean +/- SEM) particles/mm(2) for polystyrene particles and 31 +/- 7 particles/mm(2) for PSA-PEG particles] compared to the level of adhesion to wild type mouse aorta (18 +/- 1 particles/mm(2) for polystyrene particles and 6 +/- 1 particles/mm(2) for PSA-PEG particles). Within ApoE(-/-) mice, the alpha-VCAM-1 particles exhibited significantly greater adhesion to the aorta (32 +/- 5 particles/mm(2) for polystyrene particles and 31 +/- 7 particles/mm(2) for PSA-PEG particles) compared to the adhesion of IgG particles (1 +/- 1 particles/mm(2) for polystyrene particles and 2 +/- 1 particles/mm(2) for PSA-PEG particles). Detailed analysis of the adhesion revealed that alpha-VCAM-1 particles exhibited focal adhesion to plaque regions, in particular the periphery of the plaques, within the ApoE(-/-) mouse aorta. Combined the data demonstrate that polymeric particles conjugated with a ligand to VCAM-1 exhibit selective, avid and focal adhesion to sites of atherosclerosis providing strong evidence that VCAM-1 ligand bearing polymeric particles could be used for targeting drugs selectively to atherosclerotic tissue.
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PMID:Polymeric particles conjugated with a ligand to VCAM-1 exhibit selective, avid, and focal adhesion to sites of atherosclerosis. 1842 14

Accurate imaging of atherosclerosis is a growing necessity for timely treatment of the disease. Magnetic resonance imaging (MRI) is a promising technique for plaque imaging. The goal of this study was to create polymeric particles of a small size with high loading of diethylenetriaminepentaacetic acid gadolinium (III) (Gd-DTPA) and demonstrate their usefulness for MRI. A water-in-oil-in-oil double emulsion solvent evaporation technique was used to encapsulate the MRI agent in a poly(lactide-co-glycolide) (PLGA) or polylactide-poly(ethylene glycol) (PLA-PEG) particle for the purpose of concentrating the agent at an imaging site. PLGA particles with two separate average sizes of 1.83 microm and 920 nm, and PLA-PEG particles with a mean diameter of 952 nm were created. Loading of up to 30 wt % Gd-DTPA was achieved, and in vitro release occurred over 5 h. PLGA particles had highly negative zeta potentials, whereas the particles incorporating PEG had zeta potentials closer to neutral. Cytotoxicity of the particles on human umbilical vein endothelial cells (HUVEC) was shown to be minimal. The ability of the polymeric contrast agent formulation to create contrast was similar to that of Gd-DTPA alone. These results demonstrate the possible utility of the contrast agent-loaded polymeric particles for plaque detection with MRI.
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PMID:Preparation and initial characterization of biodegradable particles containing gadolinium-DTPA contrast agent for enhanced MRI. 1879 5

Calcific aortic stenosis displays some similarities to atherosclerosis including evidence of endothelial dysfunction. Whether nitric oxide (NO), which is produced by valvular endothelium, has direct protective effects extending to calcification processes in aortic valve cells has not previously been examined. In vitro calcifying nodules in porcine aortic valve interstitial cell cultures, formed in response to transforming growth factor-beta1 (TGF-beta1) 5 ng/ml, were inhibited by NO donors DETA-NONOate 5-100 microM, and sodium nitroprusside (SNP) 3 microM. Raising intracellular cGMP concentrations, via 8-bromo cGMP 1 mM or via brain natiuretic peptide and C-type natiuretic peptide 0.1 microM, inhibited TGF-beta1-induced nodule formation, potentially implicating the cGMP pathway in the NO effect. Stimulation of interstitial cells with substance P or calcium ionophone (A23187) caused NO release and increased intracellular cGMP respectively. However in the presence of TGF-beta1 basal levels of NO production via nitric oxide synthase (NOS) were insufficient to affect nodule formation. Increased dihydroethidium (DHE) fluorescence in response to TGF-beta1, which was inhibited by DETA-NONOate and TEMPOL, suggested a role for intracellular superoxide in TGF-beta1 signalling. Moreover, nodule formation was suppressed by superoxide scavengers TEMPOL, hydralazine and polyethylene glycol-superoxide dismutase (PEG-SOD), but not SOD. In conclusion, NO donors, or agents raising intracellular cGMP levels, may protect aortic valve interstitial cells from early events leading to calcification.
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PMID:Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors. 1905 77

Vulnerable or high-risk atherosclerotic plaques often exhibit large lipid cores and thin fibrous caps that can lead to deadly vascular events when they rupture. In this study, polyethylene glycol (PEG)-micelles that incorporate a gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) amphiphile were used as an MR contrast agent. In an approach inspired by lipoproteins, the micelles were functionalized with tyrosine residues, an aromatic, lipophilic amino acid, to reach the lipid-rich areas of atherosclerotic plaque in a highly efficient manner. These micelles were applied to apolipoprotein E(-/-) (ApoE(-/-)) mice as a model of atherosclerosis. The abdominal aortas of the animals were imaged using T(1)-weighted (T(1)W) high-resolution MRI at 9.4T before and up to 48 h after the administration of the micelles. PEG-micelles modified with 15% tyrosine residues yielded a significant enhancement of the abdominal aortic wall at 6 and 24 h postinjection (pi) as compared to unmodified micelles. Fluorescence microscopy on histological sections of the abdominal aorta showed a correlation between lipid-rich areas and the distribution of the functionalized contrast agent in plaque. Using a simple approach, we demonstrated that lipid-rich areas in atherosclerotic plaque of ApoE(-/-) mice can be detected by MRI using Gd-DTPA micelles.
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PMID:Tyrosine polyethylene glycol (PEG)-micelle magnetic resonance contrast agent for the detection of lipid rich areas in atherosclerotic plaque. 1978 Jan 53

The ability of cells to migrate in response to mechanical gradients (durotaxis) and differential cell behavior in adhesion, spreading, and proliferation in response to substrate rigidity are key factors both in tissue engineering, in which materials must be selected to provide the appropriate mechanical signals, and in studies of mechanisms of diseases such as cancer and atherosclerosis, in which changes in tissue stiffness may inform cell behavior. Using poly(ethylene glycol) diacrylate hydrogels with varying polymer chain length and photolithographic patterning techniques, we are able to provide substrates with spatially patterned, tunable mechanical properties in both gradients and distinct patterns. The hydrogels can be patterned to produce anisotropic structures and exhibit patterned strain under mechanical loading. These hydrogels may be used to study cell response to substrate rigidity in both two and three dimensions and can also be used as a scaffold in tissue-engineering applications.
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PMID:PEGDA hydrogels with patterned elasticity: Novel tools for the study of cell response to substrate rigidity. 1981 65

A water-soluble, 19-mer peptide fragment of serum amyloid A called MFFD is being examined as a possible treatment for atherosclerosis. As a means of administering this drug in a sustained fashion through subcutaneous implantation, a biodegradable network formulation was prepared. The formulation consisted of 1000 and 4000Da alpha,omega-diacrylate oligo(d,l-lactide)-b-poly(ethylene glycol)-b-oligo(d,l-lactide) (DLPEGDLDA) copolymerized with 2700 and 5000Da omega,omega,omega-triacrylate star-poly(epsilon-caprolactone-co-d,l-lactide) using UV irradiation. The influence on the network properties and degradation rate of the network on the amount and type of DLPEGDLDA copolymerized with the two different molecular weight ASCPs were examined in vitro. The networks degraded by bulk hydrolysis at a rate controlled primarily by the molecular weight of the ASCP used. Nevertheless, all the networks were completely degraded within 16 weeks. The MFFD was released in a diffusional manner at a rate influenced by the degree of swelling of the network and the molecular weight of the ASCP used; using an ASCP of a lower molecular weight for a given DLPEGDLDA resulted in a slower release rate. The degree of swelling of the networks was controlled solely by the nature of the PEG used in preparing the DLPEGDLDA, with greater swelling observed with higher PEG molecular weight and for greater amounts of PEG incorporation. The MFFD was not degraded during the photocrosslinking reaction or by potential acidic degradation products that may have accumulated within the device. This formulation provides a means of achieving a desirable release rate from a degradable, water-swellable network through selection of ASCP molecular weight and DLPEGDLDA composition.
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PMID:Anti-atherosclerotic peptide delivery from a photocrosslinkable biodegradable network. 2002 44

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