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)

Ras has a key role in relation to cell proliferation, survival and migration and requires farnesylation for full activity. The effects of a Ras farnesyl transferase inhibitor, FPT III on human atherosclerotic vascular smooth muscle (VSM) cells proliferation and p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) activity was measured. In addition the ability of FPT III to modify the development of neointimal growth was tested in cultured human arteries and in a rabbit model of in-stent restenosis. In human VSM cells FPT III (25 microM) inhibited FCS-stimulated cell proliferation through a ras-dependent mechanism (after 18 h exposure) and also a novel ras-independent mechanism (following 15 min exposure). FPT III incubation (18 h) inhibited platelet-derived growth factor (PDGF)-stimulated p42/p44 MAPK activation and p21 Ras membrane localization, whereas 15 min incubation had no effect on the activation of p42/p44 MAPK in response to PDGF (added at 18 h) or on membrane p21 Ras localization (measured at 18 h). In cultured human atherosclerotic arteries, the presence of 25 microM FPT III significantly reduced neointimal growth. In vivo, 15 min local infusion of 25 microM FPT III significantly reduced in-stent restenosis 28 days later without affecting vascular function in normal rabbit artery. This study demonstrates that brief administration of a farnesyl transferase inhibitor reduced in-stent restenosis in a rabbit model without deleterious effects on vascular function or endothelial regrowth. Acute application of FPT III was found to act through a novel mechanism to inhibit smooth muscle cell proliferation via a non-ras pathway, which may contribute to the prevention of in-stent restenosis.
Atherosclerosis 2008 Apr
PMID:Inhibition of non-Ras protein farnesylation reduces in-stent restenosis. 1766 87

Although turmeric (Curcuma longa; an Indian spice) has been described in Ayurveda, as a treatment for inflammatory diseases and is referred by different names in different cultures, the active principle called curcumin or diferuloylmethane, a yellow pigment present in turmeric (curry powder) has been shown to exhibit numerous activities. Extensive research over the last half century has revealed several important functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By modulating the activation of various transcription factors, curcumin regulates the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Curcumin also downregulates cyclin D1, cyclin E and MDM2; and upregulates p21, p27, and p53. Various preclinical cell culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive agent; and as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis. Pilot phase I clinical trials have shown curcumin to be safe even when consumed at a daily dose of 12g for 3 months. Other clinical trials suggest a potential therapeutic role for curcumin in diseases such as familial adenomatous polyposis, inflammatory bowel disease, ulcerative colitis, colon cancer, pancreatic cancer, hypercholesteremia, atherosclerosis, pancreatitis, psoriasis, chronic anterior uveitis and arthritis. Thus, curcumin, a spice once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin".
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PMID:Curcumin as "Curecumin": from kitchen to clinic. 1790 May 36

Migration and proliferation of vascular smooth muscle cells (VSMCs) are important events in the progression of atherosclerosis. Insulin-like growth factor I (IGF-1) possesses both antiapoptotic and mitogenic/motogenic effects in VSMCs although the influence of life cycle on IGF-1-induced effects is unclear. This study was designed to evaluate the effect of IGF-1 on migration, proliferation, and signaling mechanisms in VSMCs from early (3-5) to late (20-22) passages. Migration, proliferation, and cell survival were measured using monolayer wounding, 3[H]-thymidine incorporation and MTT assay, respectively. Akt and ERK, which are critical to proliferation, differentiation and migration, were examined using Western blot analysis. DCF-DA fluorescence was used to quantify Reactive Oxygen Species (ROS) production. Late-passage VSMCs exhibited significantly higher basal cell proliferation and enhanced sensitivity to IGF-1-stimulated migration compared to cells from early-passages. Phosphorylated Akt and ERK levels were significantly higher in late-passage cells compared to early-passage, which was further enhanced by IGF-1 treatment. Late-passage cells exhibited higher levels of ROS production compared to early-passage, cells. IGF-1 did not significantly alter ROS levels in either passage. Expression of the cell cycle regulator p53, p21, and p16 was not affected by repeated passaging of cells. These results indicated that repeated passaging of VSMCs exhibits a phenotype which has higher proliferative capacity. Activation of trophic signaling molecules such as ERK1/2 and Akt and generation of ROS may represent the mechanisms by which repeated passages of VSMCs acquire a motogenic and mitogenic phenotype.
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PMID:Impact of insulin-like growth factor-I on migration, proliferation and Akt-ERK signaling in early and late-passages of vascular smooth muscle cells. 1796 Apr 99

Ginkgo biloba extract (GBE) has been widely used to treat cardiovascular and cerebrovascular disorders. Hyperhomocysteinemia (Hhcy) is associated with the risk of atherosclerosis and restenosis after angioplasty. The objective of this study was to investigate whether GBE could attenuate the Hhcy-induced intimal thickening after balloon injury in rabbit abdominal aorta. It was observed in this study that GBE could decrease the neointima area (NA) and the ratio of the neointima area to the media area (NA/MA), down-regulate the mRNA expression of matrix metalloproteinase-9 (MMP-9) and up-regulate the protein expression of p21 (WAF1/CIP1) (p21). It suggests that GBE can reverse the Hhcy-induced neointima formation in rabbits following balloon injury, and the suppressive effect of GBE on the migration and proliferation of vascular smooth muscle cells (VSMCs) may contribute to its actions.
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PMID:Inhibitory effect of Ginkgo biloba extract on hyperhomocysteinemia-induced intimal thickening in rabbit abdominal aorta after balloon injury. 1816 42

RGD-peptides can inhibit the binding of ligands to certain beta3 integrins, alphaIIbbeta3 and alphavbeta3, both of which are involved in neointimal hyperplasia that contributes to atherosclerosis and restenosis of arterial walls. Saxatilin, a disintegrin from a Korean snake (Gloydius saxatilis), interacts with integrins alphaIIbbeta3 and alphavbeta3. It suppressed the adhesion of human coronary artery smooth muscle cells (HCASMCs) to vitronectin with an IC(50) of 2.5 microM, and growth factor (PDGF-BB or bFGF)-induced proliferation was inhibited at an IC(50) of 25 microM. Saxatilin disassembled the actin cytoskeleton of focal adhesion and induced cell detachment. This disassembly of focal adhesion in saxatilin-treated HCASMCs involved caspase-induced paxillin degradation. Saxatilin temporally phosphorylated FAK and ERKs and affected the cell cycle of HCASMCs by increasing CDK inhibitors (p21 and p27) and reducing cyclins (D1/2 and E). These results may have significant implications for integrin antagonistic therapy used for the treatment of atherosclerosis and restenosis.
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PMID:Suppressive effect and mechanism of saxatilin, a disintegrin from Korean snake (Gloydius saxatilis), in vascular smooth muscle cells. 1862 63

Disturbed blood flow induces inflammatory gene expression in endothelial cells, which promotes atherosclerosis. Flow stimulates the proinflammatory transcription factor nuclear factor (NF)-kappaB through integrin- and Rac-dependent production of reactive oxygen species (ROS). Previous work demonstrated that NF-kappaB activation by flow is matrix-specific, occurring in cells on fibronectin but not collagen. Activation of p21-activated kinase (PAK) followed the same matrix-dependent pattern. We now show that inhibiting PAK in cells on fibronectin blocked NF-kappaB activation by both laminar and oscillatory flow in vitro and at sites of disturbed flow in vivo. Constitutively active PAK rescued flow-induced NF-kappaB activation in cells on collagen. Surprisingly, PAK was not required for flow-induced ROS production. Instead, PAK modulated the ability of ROS to activate the NF-kappaB pathway. These data demonstrate that PAK controls NF-kappaB activation by modulating the sensitivity of cells to ROS.
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PMID:p21-activated kinase signaling regulates oxidant-dependent NF-kappa B activation by flow. 1879 40

S-diclofenac (2-[(2,6-dichlorophenyl) amino] benzene acetic acid 4-(3H-1,2,dithiol-3-thione-5-yl) phenyl ester) is a novel molecule comprising a hydrogen sulfide (H2S)-releasing dithiol-thione moiety attached by an ester linkage to diclofenac. Effect of S-diclofenac (H2S donor) on cell proliferation was investigated on the primary and immortalized rat aortic vascular smooth muscle cells (SMC). Smooth muscle cell proliferation has been considered as a key event in vascular injury in diseases such as atherosclerosis and restenosis after invasive intervention. Clonogenic cell survival assay showed a dose dependent (10-100 microM) decrease in cell survival. Flow cytometric analysis showed that the asynchronized cells are more sensitive than the cells that are synchronized and revealed that the cells in G1 phase are not affected by the treatment of the S-diclofenac. Asynchronized smooth muscle cells treated with the S-diclofenac showed an increase in apoptotic cell death. S-diclofenac treatment also resulted in stabilization of p53 coupled with the induction of downstream proteins such as p21, p53AIP1 and Bax. S-diclofenac did not up-regulate cell levels of the antiapoptotic protein Bcl-2. However, when the cells are synchronized a stimulatory effect of cell growth with the decrease in apoptosis, p53 and p21 was evident. S-diclofenac inhibits smooth muscle cell growth and may play a role in the lesion formation at sites of the vascular injury. The present results suggest that S-diclofenac may be useful for the prevention of smooth muscle cell proliferation in diseases such as vascular obstructive and restenosis.
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PMID:Effect of S-diclofenac, a novel hydrogen sulfide releasing derivative inhibit rat vascular smooth muscle cell proliferation. 1868 Jul 41

Simvastatin was reported to attenuate platelet-derived growth factor (PDGF)-induced vascular smooth muscle proliferation by up-regulation of cyclin dependent kinase (CDK) inhibitor p27, but had no effect on p16, p21, p53 expression. We investigate the mechanisms by which simvastatin inhibits vascular smooth muscle cell (VSMC) growth in high glucose conditions to mimic diabetes. Simvastatin was added to A7r5 cells cultured in high glucose (25 mM) medium, mimicking diabetes. We used an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate cell viability; flow cytometric analysis for cell counts distribution in the cell cycle; and Western blot, immunoblotting, and immunoprecipitation analyses to evaluate the effects of simvastatin on CDK activity and cell cycle regulatory proteins. Cell counts were significantly increased in G0/G1 phase and significantly decreased in S and G2/M phases. In our study, low dose of simvastatin had no significant inhibitory effect on VSMC growth in normal glucose condition. However, both low and high doses of simvastatin inhibited VSMC growth significantly in a dose-dependent manner in high glucose status. We also found that simvastatin inhibited phosphorylation of Rb, promoted expression of p53, p16, p21, p27 and decreased CDK2/4 activity. In conclusion, simvastatin inhibits VSMC proliferation in high glucose status, mimicking diabetes, inducing a G0/G1 phase cell cycle growth arrest by acting on multiple steps upstream of pRb, including inhibition of CDK2/4 expression and up-regulation of p53, p21, p16, and p27. We propose that statins may be used more extensively in diabetic patients regardless of lipid status for preventing atherosclerosis and restenosis after PCI.
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PMID:Simvastatin inhibits cell cycle progression in glucose-stimulated proliferation of aortic vascular smooth muscle cells by up-regulating cyclin dependent kinase inhibitors and p53. 1880 36

Premature aging (senescence) of endothelial cells might play an important role in the development and progression of hypertension and atherosclerosis. We hypothesized that bradykinin, a hormone that mediates vasoprotective effects of angiotensin-converting enzyme inhibitors, protects endothelial cells from oxidative stress-induced senescence. Bradykinin treatment (0.001 to 1 nmol/L) dose-dependently decreased senescence induced by 25 micromol/L of H(2)O(2) in cultured bovine aortic endothelial cells, as witnessed by a complete inhibition of increased senescent cell numbers and a 34% reduction of the levels of the senescence-associated cell cycle protein p21. Because H(2)O(2) induces senescence through superoxide-induced DNA damage, single-cell DNA damage was measured by comet assay. Bradykinin reduced DNA damage to control levels. The protective effect of bradykinin also resulted in a significant increase in the migration of H(2)O(2)-treated bovine aorta endothelial cells in an in vitro endothelial injury model, or "scratch" assay. The protective effect of bradykinin was abolished by the bradykinin B2 receptor antagonist HOE-140 and the NO production inhibitor N(omega)-methyl-L-arginine acetate salt. Therefore, we conclude that bradykinin protects endothelial cells from superoxide-induced senescence through bradykinin B2 receptor- and NO-mediated inhibition of DNA damage.
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PMID:Bradykinin protects against oxidative stress-induced endothelial cell senescence. 1907 96

Atherosclerosis begins as local inflammation of artery walls at sites of disturbed flow. JNK (c-Jun NH(2)-terminal kinase) is thought to be among the major regulators of flow-dependent inflammatory gene expression in endothelial cells in atherosclerosis. We now show that JNK activation by both onset of laminar flow and long-term oscillatory flow is matrix-specific, with enhanced activation on fibronectin compared to basement membrane protein or collagen. Flow-induced JNK activation on fibronectin requires new integrin ligation and requires both the mitogen-activated protein kinase kinase MKK4 and p21-activated kinase. In vivo, JNK activation at sites of early atherogenesis correlates with the deposition of fibronectin. Inhibiting p21-activated kinase reduces JNK activation in atheroprone regions of the vasculature in vivo. These results identify JNK as a matrix-specific, flow-activated inflammatory event. Together with other studies, these data elucidate a network of matrix-specific pathways that determine inflammatory events in response to fluid shear stress.
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PMID:The subendothelial extracellular matrix modulates JNK activation by flow. 1939 61


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