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)

In the last decade, the understanding of the molecular mechanisms of regulation of the inflammatory process in chronic inflammatory diseases has moved remarkably forward. Recent evidence in various fields has consistently indicated that T-cells play a key role in initiating and perpetuating inflammation, not only via the production of soluble mediators but also via cell/cell contact interactions with a variety of cell types through membrane receptors and their ligands. Signalling through CD40 and CD40 ligand is a versatile pathway that is potently involved in all these processes. In this article, we review how T-cells become activated by dendritic cells or inflammatory cytokines, and how these T-cells activate, in turn, monocytes/macrophages, endothelial cells, smooth muscle cells and fibroblasts to produce pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin-6), chemokines (interleukin-8, monocyte chemotactic protein-1), tissue factor, the main initiator of the coagulation cascade in vivo, and finally matrix metalloproteinases, responsible for tissue destruction. Moreover, we discuss how CD40 ligand at inflammatory sites stimulates fibroblasts and tissue monocyte/macrophage production of VEGF, leading to angiogenesis, which promotes and maintains the chronic inflammatory process. This cascade of events is discussed in the context of disease initiation/progression, with particular reference to atherosclerosis and rheumatoid arthritis, and to potential novel therapeutic targets for their treatment.
 ...
PMID:T-cell-mediated signalling in immune, inflammatory and angiogenic processes: the cascade of events leading to inflammatory diseases. 1503 40

Although the VEGF-Flk-1-pathway has been known as the major driving force of angiogenesis, new evidence has shown that VEGFR-1/Flt-1 plays important roles during the neovascularization under pathological conditions including tumor, atherosclerosis and arthritis. In search of Flt-1 receptor antagonizing peptides, we screened a phage display 12-mer-peptide library with recombinant Flt-1 protein. Seven candidate peptides were identified that specifically bound to VEGF receptor Flt-1, of which peptide F56 (WHSDMEWWYLLG) almost abolished VEGF binding to receptor Flt-1 in vitro. In vivo, F56 fused with DHFR (DHFR-F56) inhibited angiogenesis in a CAM assay. Moreover, DHFR-F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice. Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with DHFR-F56. In the severe combined immunodeficiency disease (SCID) mouse model for studying metastasis of the human breast cancer cell line BICR-H1, synthetic peptide F56 significantly inhibited tumor growth and lung metastases. Taken together, our results have demonstrated that peptide F56, as a Flt-1 receptor antagonist, fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between VEGF and receptor Flt-1. Thus, short peptide F56 may have clinical potential in tumor therapy.
 ...
PMID:Suppression of tumor growth and metastasis by a VEGFR-1 antagonizing peptide identified from a phage display library. 1519 67

Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes. Because activation of NF-kappaB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NF-kappaB activation. In the present study, we tested this hypothesis by investigating the effect of this steroid on the activation of NF-kappaB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NF-kappaB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1. NF-kappaB activation was not cell type-specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NF-kappaB activation expressed in most tumor cells. Through inhibition of IkappaB kinase activation, this steroid blocked IkappaBalpha phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65-mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti-apoptosis (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), proliferation (cyclin D1 and c-Myc), and metastasis (MMP-9, COX-2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Overall, our results indicate that guggulsterone suppresses NF-kappaB and NF-kappaB-regulated gene products, which may explain its anti-inflammatory activities.
 ...
PMID:Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. 1532 87

Elevation of plasma VEGF (vascular endothelial growth factor) has been noted in patients with hypertension or atherosclerosis. VEGF has been regarded as a marker for endothelial dysfunction. However, the role of VEGF in hypertension-induced vascular injury and its relationship with endothelial function have not been studied. This study included 20 untreated hypertensive men with grade 1 or 2 hypertensive retinopathy, 10 untreated hypertensive men without hypertensive retinopathy and 10 healthy controls. None of the hypertensive patients had diabetes, renal impairment or overt vascular diseases. Plasma VEGF and adhesion molecules were measured using ELISAs. Endothelial function was measured by FMD (flow-mediated vasodilation) of the brachial artery. Plasma levels of VEGF, excluding adhesion molecules, were significantly higher in hypertensive patients with retinopathy when compared with patients without retinopathy (152.4+/-80.8 pg/ml versus 104.7+/-27.2 pg/ml, P = 0.035) or controls (152.4+/-80.8 pg/ml versus 98.9+/-23.7 pg/ml, P = 0.025). Levels of FMD were significantly lower in hypertensive patients than controls, but there were no significant differences between patients with or without retinopathy. Degrees of FMD were inversely correlated with VEGF levels (r = -0.351, P = 0.031). Elevation of plasma VEGF was associated with hypertensive retinopathy. Plasma VEGF could be used as a marker of early vascular damage induced by hypertension.
 ...
PMID:Plasma vascular endothelial growth factor as a marker for early vascular damage in hypertension. 1574 Apr 59

Little information regarding the development of lymphangiogenesis in coronary atherosclerosis is available. We immunohistochemically investigated the correlation among intimal neovascularization (CD34 for angiogenesis and lymphatic vessel endothelial hyaluronan receptor-1 [LYVE-1] and podoplanin for lymphangiogenesis), the expression of lymphangiogenic factors (vascular endothelial growth factor [VEGF]-C and VEGF-D), and the progression of atherosclerosis using 169 sections of human coronary arteries from 23 autopsy cases. The more the atherosclerosis advanced, the more often the neointimas contained newly formed blood vessels ( P < .0001). Vascular endothelial growth factor-C was expressed mostly in foamy macrophages and in some smooth muscle cells, whereas VEGF-D was abundantly expressed in both. The number of VEGF-C-expressing cells, but not that of VEGF-D-expressing cells, was increased as the lesion advanced and the number of intimal blood vessels increased ( P < .01). Lymphatic vessels were rare in the atherosclerotic intima (LYVE-1 vs CD34 = 13 vs 3955 vessels) compared with the number seen in the adventitia (LYVE-1 vs CD34 = 360 vs 6921 vessels). The current study suggests that VEGF-C, but not VEGF-D, may contribute to plaque progression and be a regulator for angiogenesis rather than lymphangiogenesis in coronary atherosclerotic intimas. Imbalance of angiogenesis and lymphangiogenesis may be a factor contributing to sustained inflammatory reaction during human coronary atherogenesis.
 ...
PMID:Angiogenesis and lymphangiogenesis and expression of lymphangiogenic factors in the atherosclerotic intima of human coronary arteries. 1589 93

Nicotine, a component of cigarette smoke, has been implicated in the pathogenesis of cardiovascular disease. We examined whether nicotine regulates angiotensin-converting enzyme (ACE), an enzyme that plays an important role in the pathophysiology of atherosclerosis and hypertension. Human umbilical cord vein endothelial cells were treated with nicotine (0.1-1 microM) alone or in combination with vascular endothelial growth factor (VEGF; 0.5 nM) or GF-109203X (GFX; 2.5 microM). The amount of ACE in intact endothelial cells was measured by an inhibitor-binding assay method, and ACE mRNA levels were quantified using LightCycler technology. Phosphorylated PKC levels were measured by Western immunoblotting. Nicotine did not modulate basal ACE production but significantly potentiated VEGF-induced ACE upregulation. Treatment of endothelial cells with the PKC inhibitor GFX totally blocked VEGF- and nicotine-induced ACE upregulation. VEGF induced PKC phosphorylation, which was potentiated by cotreatment with nicotine. We conclude that nicotine significantly potentiated VEGF-induced ACE upregulation. This effect was probably mediated by PKC phosphorylation. The interaction of nicotine with VEGF in ACE induction may contribute to the pathogenesis of smoking-related cardiovascular disease.
 ...
PMID:Regulation of angiotensin-converting enzyme production by nicotine in human endothelial cells. 1596 16

Endothelial dysfunction is an early sign of atherosclerosis. Patients with risk factors for atherosclerosis (e.g., hypertension, hyperlipidemia and diabetes mellitus) often show endothelial dysfunction at early stages of atherosclerosis before cardiovascular complications develop. Clinical studies and basic researches are revealing that calcium antagonists not only protect the endothelium through their hypotensive action but also improve the endothelial function through the stimulation of NO production. Regarding the mechanism for this kind of action by nifedipine (a calcium antagonist), it seems likely that the drug stimulates SOD expression in endothelial cells through enhanced VEGF expression by vascular smooth muscle cells, and thus reduces oxidative stress, leading to increased NO production.
 ...
PMID:[Calcium antagonists and endothelial function]. 1619 12

Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations harbor genetic variations that alter angiogenesis. Some of these changes result in Mendelian traits of variable penetrance, with telangiectasia being a common symptom. Other more subtle variations exist, with promoter variations in the VEGF gene being of particular interest. Genetic diversity in angiogenesis-regulating genes has been linked to increased susceptibility to multiple angiogenesis-dependent diseases in humans. These diseases include cancer, arthritis, atherosclerosis, and cardiovascular disease, endometriosis, diabetic retinopathy, retinopathy of prematurity, psoriasis, and sarcoidosis. Also, multiple disturbances in pregnancy including miscarriage, spontaneous preterm delivery, and severe pre-eclampsia have been linked to alterations in angiogenesis-regulating genes. Present efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Ongoing mapping studies have identified multiple loci that control angiogenic responsiveness in several mouse models. Genetic alterations responsible for discrete angiogenic alterations will then be studied in appropriate mouse disease models.
 ...
PMID:The effect of genetic diversity on angiogenesis. 1632 83

Negative arterial remodeling still plays an important role in the pathogenesis of coronary restenosis even in the era of interventional stenting (e.g. arterial narrowing occurs proximal and distal of a stented segment). Previous studies suggest that increased angiogenesis and inhibited regression of injury-induced adventitial microvessels prevents negative remodeling. We have examined the effect of local vascular endothelial growth factor (VEGF(165)) gene transfer on adventitial microvessel angiogenesis/regression and arterial remodeling after coronary angioplasty. Twenty pigs underwent angioplasty, each one in two major coronary arteries, followed by plasmid liposome gene transfer with either VEGF(165) or control gene LacZ (50 microg DNA with 50 microg of Lipofectine) into the (peri)adventitial space using a needle injection catheter. Arteries were examined at days 1, 7, 14, and 28. Local delivery of VEGF(165) gene into the outer compartments of balloon-injured porcine coronary arteries reduced lumen area loss due to distinct positive remodeling (arterial enlargement). Prevention of adventitial microvessel regression, enhanced adventitial elastin accumulation, reduced adventitial myofibroblast numbers, and a pronounced adventitial inflammatory response considered as a part of arterial healing seem to be the main VEGF-mediated mechanisms indicating the therapeutic potential of VEGF for restenosis prevention.
Atherosclerosis 2006 Nov
PMID:Adventitial VEGF165 gene transfer prevents lumen loss through induction of positive arterial remodeling after PTCA in porcine coronary arteries. 1643 47

Recent data from animal models has demonstrated that both endothelial and smooth muscle progenitor cells contribute to the development of atherosclerosis. However, no data exists concerning the presence of progenitor cells in human atherosclerotic vessels. In the present study, a range of normal and atherosclerotic human arteries were collected from patients undergoing coronary artery bypass surgery. Segments of internal mammary artery (normal controls), and segments of proximal ascending aorta with visible fatty streak were analysed. Immunofluorescence was used to detect a panel of progenitor cell markers. A small number of progenitor cells were identified within neointimal lesions and the adventitia with variable expression of CD34, stem cell antigen (Sca-1), c-kit and VEGF receptor 2 (VEGFR2) markers, but no CD133 expression. On average there was a two- to three-fold increase in progenitor cell number in the adventitia of atherosclerotic vessels compared with normal controls, with a significant difference (p<0.05) in the frequency of cells expressing VEGFR2. Thus, we have provided the first evidence that vascular progenitor cells exist within atherosclerotic lesions, and identified an increased number of progenitor cells in the adventitia of human atherosclerotic vessels. These cells might be a source for smooth muscle cells (SMCs), macrophages and endothelial cells (ECs) that form atherosclerotic lesions.
Atherosclerosis 2007 Apr
PMID:Characterisation of progenitor cells in human atherosclerotic vessels. 1678 46


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