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)

In atherosclerosis numerous qualitative and quantitative changes in connective tissue metabolism parameters in serum and aorta occur. In atherosclerosis there is an enhanced activity of local renin-angiotensin systems. It leads to overexpression of ANG II, both in serum and arterial wall. ANG II stimulates SMC to over-synthesize the collagens type I and III. Hyper-cholesterolemia is a form of metabolic injury which can both induce phenotypic change of SMC and activate RA system in arterial wall. ACEI lower the accumulation of collagens type I and III, and enhance elastin content in arterial wall in experimental hypertension. The aim of this study was to assess the influence of captopril, enalapril and quinapril on connective tissue metabolism of the aorta in experimental hyper-cholesterolemia. 64 male New Zealand rabbits were used. Animals were fed with standard fodder, special diet (1% cholesterol content) or special diet + tested ACEI. Two doses of ACE inhibitors were used: 1st--equivalent to doses applied to human subjects (in mg/kg of body weight), 2nd--dose 10 times higher. The animals were divided into 8 equal groups: K--standard fodder, B--special diet, C1, C2--special diet + captopril in doses 2.5 and 25 mg/kg/24 hours, respectively, E1, E2--special diet + enalapril in doses 0.75 and 7.5 mg/kg/24 hours, respectively, Q1 i Q2--special diet + quinapril in doses 0.75 and 7.5 mg/kg per day, respectively. The experiment lasted for 6 months. After 24 weeks the animals were sacrificed and aortae were excised for collagens assay. The statistical analysis was performed using ANOVA, followed by LSD test; p < 0.05 was considered statistically significant. The aorta collagens content of cholesterol-fed rabbits significantly increased. The tested ACEI (captopril, enalapril in both doses and quinapril in lower dose) had a preventive effect against the increase of aorta collagen content.
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PMID:[The influence of angiotensin-converting enzyme inhibitors on collagen content of the aorta wall in experimental hypercholesterolemia]. 1080 May 84

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.
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PMID:Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells. 1102 84

Endoglin is a transmembrane protein that is found in association with transforming growth factor-beta (TGF-beta) superfamily receptor complexes and has an expression pattern that appears to be restricted primarily to endothelial cells, activated macrophages, trophoblasts, and fibroblasts. Since mutations in endoglin have been shown to be linked to hereditary hemorrhagic telangiectasia type 1, a disease manifested as vascular malformations characterized by excessive layers of vascular smooth muscle cells (VSMC), the expression of endoglin was investigated in VSMC. In vivo, the majority of SMC in human atherosclerotic plaques expressed high levels of endoglin, while endoglin was not detected in SMC from samples of the normal arterial wall. In vitro studies demonstrate that human aortic smooth muscle cells (HASMC) express the L-isoform of endoglin. Like endothelial cells, HASMC express endoglin protein as a dimer on the cell surface that binds TGF-beta1. In vitro, endoglin expression by HASMC is upregulated in response to TGF-beta1, suggesting that the presence of this factor in the atherosclerotic plaque might be responsible for the increased expression of endoglin. The demonstration of increased levels of endoglin in VSMC in human atherosclerotic plaques suggests a role for SMC endoglin in the maintenance of vascular integrity and in the response of the vessel wall to injury.
Atherosclerosis 2000 Dec
PMID:Endoglin, a TGF-beta receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques. 1116 21

The objective here is to inquire what kind of coronary artery is it that tends to acquire atheroma: When an atheroma is found somewhere in the specimen (YesA specimen), what do we see in the specimen far away from the atheroma? Previous studies found thicker intima in YesA specimens than in NoA specimens, but with equal numbers of smooth muscle cells (SMC's). Thickness per SMC strongly predicted atheroma, so much so that the risk factor age was fully explained statistically. This study now finds that the medial layer is also thicker in YesA specimens, and with medial SMC numbers equal to those in NoA specimens. Hence, the aging risk factor appears to induce excessive thickness per SMC as a generalized property throughout the whole specimen in the medial as well as intimal layers, with excessive production of collagenous matrix acting as an initial, rate limiting step in plaque formation. In the intima, atheroma tends to occur when average thickness per SMC exceeds the threshold value of 8.6 microm/SMC. The extreme high value found in the most severely affected medial sample was 4.2 microm/SMC, and this failure to approach the threshold could explain the medial resistance to fatty degenerations.
Atherosclerosis 2001 Apr
PMID:Medial thickenings of coronary artery and the aging risk factor for atherosclerosis. 1125 4

The phenotypic modulation of vascular smooth muscle cells (VSMCs) from the differentiated state to the dedifferentiated one is critically involved in the development and progression of atherosclerosis. Although many cytokines and growth factors have been reported as atherogenic factors, the critical pathogens for inducing atherosclerosis remain unknown, largely because proper examining systems of them have not been developed. We recently established primary culture systems for visceral SMCs and VSMCs in which both SMCs, when cultured on laminin with insulin-like growth factor-I, show a differentiated phenotype, as indicated by a spindle-like shape, ligand-induced contractility, and a high level of SMC differentiation marker gene expression. In this study, we searched for critical dedifferentiation factors for these SMCs using our culture system. We found that polar lipids extracted from human serum markedly induced VSMC dedifferentiation, and this activity was solely present in the lysophosphatidic acid (LPA) fraction. Among several LPA species detected in human serum lipids, unsaturated LPAs were identified as major contributors to the induction of VSMC dedifferentiation. Signaling and phenotype analyses revealed that unsaturated LPA-induced VSMC dedifferentiation is mediated through the coordinated activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. Thus, this report demonstrates the first finding that unsaturated LPAs, but not saturated LPAs, specifically induce VSMC phenotypic modulation, suggesting that these molecules could function as atherogenic factors.
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PMID:Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids. 1148 75

The aim of this study was to evaluate the proliferative behavior of vascular smooth muscle cells in primary culture (pC-SMC) and the endothelial nitric oxide synthase (eNOS) activity in the endothelial lining of the aorta of fructose-fed rats (FFR). This is an experimental model of syndrome X, a cluster of cardiovascular risk factors including hyperinsulinemia, insulin resistance, and hypertension that has been suggested to be of pathophysiologic importance for the development of atherosclerosis. Male Wistar rats were used: Control (n = 12) and FFR (n = 12). After receiving fructose in drinking water (10% w/v) during 8 weeks, biochemical parameters, systolic blood pressure (SBP) and relative heart weight (RHW) were determined. The proliferative effect of 10% fetal calf serum (FCS) was examined in aortic pC-SMC by [3H]thymidine incorporation and by cell counting. Ca2+/calmodulin-dependent NOS activity was estimated in aortic endothelial lining and in heart tissue homogenates by conversion of [3H]arginine into [3H]citrulline. Fructose-fed rats showed hyperinsulinemia (P = .0263), altered glucose tolerance test (P < .001), higher SBP (P < .0001), and RHW (P = .0145), compared to control rats. These animals also showed an increase of 10% FCS-induced [3H]thymidine incorporation (P < .0001) and cell number of aortic pC-SMC (P = .0049) and decreased eNOS activity in both aortic endothelium (P = .0147) and cardiac tissue (P < .0001). These data support the hypothesis that syndrome X is associated to changes in SMC proliferation and endothelial dysfunction, which could be involved in the onset or progression of the atherogenic process.
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PMID:Aortic smooth muscle cell proliferation and endothelial nitric oxide synthase activity in fructose-fed rats. 1172 13

Proliferation of vascular smooth muscle cells (VSMC) represents an essential event in the developement of diabetic atherosclerosis. Previous studies suggest that several cytokines and growth factors mediate the proliferation capability in VSMC from diabetic animals. In addition, advanced glycation end products (AGE) and receptor for AGE (RAGE) are important for pathologic features of diabetic complications. In the present study, we attempted to clarify the roles of AGE and RAGE in the proliferation of VSMC using streptozotocin (STZ)-treated rat sera and aortic SMC prepared from non-diabetic rats. AGE levels increased in the diabetic sera, which enhanced the growth of VSMC in proportion to their diabetic periods. AGE-bovine serum albumin (BSA) prepared in vitro also exhibited a stimulatory effect on VSMC growth. The endocytic uptake of AGE and enhanced RAGE expression in VSMC after culture with diabetic sera were observed. In addition, anti-AGE and anti-RAGE antibodies inhibited these stimulatory effects on VSMC growth. These findings suggest that AGE in diabetic rat sera may cause an enhanced effect on VSMC proliferation. However, the concentrations of AGE in diabetic sera were much lower than that of AGE-BSA which demonstrated a significant stimulatory effect on VSMC growth. The magnitude of the VSMC growth-enhancement by the diabetic sera was markedly greater than that by the AGE-BSA solution. In conclusion, the AGE-RAGE interaction in VSMC, in addition to growth factors induced by AGE, contributes to the stimulatory effect of diabetic sera on VSMC proliferation which can accelerate atherosclerosis.
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PMID:Roles of advanced glycation endproducts (AGE) and receptor for AGE on vascular smooth muscle cell growth. 1174 27

Local gene transfer into the vascular wall offers a promising alternative to treat atherosclerosis-related diseases. Blood vessels are among the easiest targets for gene therapy because of percutaneous, catheter-based treatment methods. On the other hand, gene transfer to the artery wall can also be accomplished from adventitia either by ex vivo gene transfer and implantation of transfected cells or by direct in vivo gene transfer methods. In the future, as the pathological processes in arteries are better understood, several therapeutic genes could be combined and these "gene cocktails" are expected to produce enhanced therapeutic effects in vascular gene therapy. We have developed a new, efficient technique for performing ex vivo gene transfer to rabbit arterial wall using autologous SMC. The cells were harvested from rabbit ear artery, transfected in vitro with VSV-G pseudotyped lacZ retrovirus, and returned back to the adventitial surface of the carotid artery using a silicone collar or collagen sheet placed around the artery. The transduced SMCs implanted with a high efficiency and expressed beta-galactosidase marker gene at a very high level 7 days and 14 days after the operation. The level of lacZ expression decreased thereafter, but was still easily detectable for at least 6 months and was exclusively localized to the site of cell implantation inside the collar. Development of new vectors, such as baculovirus, for gene transfer will provide targeted, efficient, and safer methods for gene delivery. Plasmids and viruses coding for more than one protein, and bearing regulatory elements, would be useful for future gene therapy applications. Also, constructing second-generation viruses that contain fewer endogenous genes in their genome may reduce immunological reactions caused by the first-generation adenoviruses. In conditions where stable expression of therapeutic proteins is needed, it is necessary to develop better ex vivo and in vivo gene transfer strategies. Also, production of viruses that can efficiently transfect nondividing cells will be important for future applications of vascular gene therapy. However, current knowledge from vascular gene transfer experiments strongly suggests that vascular gene transfer is a promising new alternative for the treatment of cardiovascular diseases.
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PMID:Gene therapy methods in cardiovascular diseases. 1188 76

The human cytomegalovirus (HCMV) has been implicated in the acceleration of vascular disease for some time. The development of vascular disease involves a chronic inflammatory process with many contributing factors, and of these, chemokines and their receptors have recently been identified as key mediators. Interestingly, HCMV encodes four potential chemokine receptors (US27, US28, UL33 and UL78). Of these virally-encoded chemokine receptors, US28 has been the most widely characterized. US28 binds many of the CC-chemokines, and this class of chemokines contributes to the development of vascular disease. Importantly, HCMV infection mediates in vitro SMC migration, which is dependent upon expression of US28 and CC-chemokine binding. US28 and the US28 functional homologues that are capable of inducing the migration of SMC represent potential targets in the treatment of CMV-accelerated vascular disease such as atherosclerosis, restenosis, and transplant vascular sclerosis.
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PMID:The HCMV chemokine receptor US28 is a potential target in vascular disease. 1245 11

Vascular smooth muscle cells (VSMCs) migration and proliferation play a key role in the pathophysiology of cardiovascular disease. However, the transcription factors that regulate VSMC activation are not completely characterized. By a mRNA-differential display approach, we have identified neuron-derived orphan receptor-1 (NOR-1), a transcription factor within the NGFI-B subfamily of nuclear receptors, as a immediate-early gene in VSMCs. Two NOR-1 isoforms (alpha and beta) were identified and cloned from serum-induced porcine VSMC that shared high homology with the human isoforms. Northern blot analysis revealed a strong and transient (1 to 6 hours) upregulation of NOR-1 in both porcine and human coronary SMCs by growth factors (serum, platelet-derived growth factor-BB, and epidermal growth factor) and alpha-thrombin but not by cytokines. NOR-1 upregulation is processed through G protein-coupled receptors and tyrosine kinase receptors, and involves Ca2+ mobilization, protein kinase C activation, and the mitogen-activated protein kinase pathway. This induction was closely dependent of the cAMP response elements present in NOR-1 promoter as transfection assays indicate. Human coronary atherosclerotic lesions overexpress NOR-1, and balloon angioplasty transiently induces NOR-1 in porcine coronary arteries with a pattern similar to that observed in VSMCs in culture. Antisense oligonucleotides against NOR-1 inhibited human coronary SMC proliferation (reduced de novo DNA synthesis, cell cycle progression, and VSMC wound repair) as efficiently as antisense against the protooncogene c-fos. These results show that NOR-1 modulates VSMC proliferation, and suggest that this transcription factor may play a role in both spontaneous and accelerated atherosclerosis.
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PMID:Neuron-derived orphan receptor-1 (NOR-1) modulates vascular smooth muscle cell proliferation. 1252 26


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