Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of atherosclerosis as well as intimal hyperplasia after vascular injury. We used Fischer rat smooth muscle cells (SMCs) overexpressing MMP-9 to determine the role of MMP-9 in migration and proliferation as well as in vessel remodeling after balloon denudation. Fischer rat SMCs were stably transfected with a cDNA for rat MMP-9 under the control of a tetracycline-regulatable promoter. In this system, MMP-9 was overexpressed in the absence, but not in the presence, of tetracycline. In vitro SMC migration was determined using a collagen invasion assay as well as a Boyden chamber assay. In vivo migration was determined by measuring the invasion into the medial and intimal layers of transduced SMCs seeded on the outside of the artery. Transduced SMCs were also seeded on the luminal surface, and the effect of local MMP-9 overexpression on vascular structure was measured morphometrically at intervals up to 28 days. MMP-9 overexpression enhanced SMC migration in both the collagen invasion assay and Boyden chamber in vitro, increased SMC migration into an arterial matrix in vivo, and altered vessel remodeling by increasing the vessel circumference, thinning the vessel wall and decreasing intimal matrix content. These results demonstrate that MMP-9 enhances vascular SMC migration in vitro and in vivo and alters postinjury vascular remodeling.
 ...
PMID:Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery. 1059 Feb 45

Effects of acute cytomegalovirus (CMV) infections on transplantation-associated atherosclerosis (TxAA) were studied in a rat model for chronic vascular rejection. Rats underwent orthotopic abdominal allogeneic aorta transplantation. Neo-intima formation and media thinning was quantitated by measurement of cross-sectional surface areas (CSA) at day 50 post transplantation (Tx). Acute rat cytomegalovirus (RCMV) infection, established at the moment of maximum intimal proliferation and influx of inflammatory cells in the adventitia, resulted in enhanced neo-intima formation, accompanied by increased influx and proliferation of smooth muscle cells (smc) in the intima. This effect was completely inhibited by HPMPC, a very potent and selective inhibitor of CMV replication, indicating the virus specificity of the measured effects. Despite increased neointima formation, media thinning ("necrosis") was not affected by RCMV infection.
 ...
PMID:Enhancement of transplantation-associated atherosclerosis by CMV, which can be prevented by antiviral therapy in the form of HPMPC. 1127 Dec 53

Atherosclerotic mouse models develop little ischemic organ damage and no infarctions, despite the presence of large atherosclerotic lesions. Therefore, we hypothesize that luminal changes do not follow atherosclerotic lesion development. Because a phenomenon that may explain the discrepancy between luminal changes and lesion size is vascular remodeling, we measured parameters of vascular remodeling in the carotid arteries (CAs), thoracic aorta (TA), and abdominal aorta (AA) of apolipoprotein E (apoE)-deficient (apoE(-/-)) and apoE*3-Leiden mice, 2 well-known mouse models of atherosclerosis. Atherosclerotic lesions were classified (American Heart Association [AHA] types II through V), and plaque thickness, compensatory enlargement versus constrictive remodeling, lumen diameter, stenosis, and media thickness were measured relative to the nondiseased arterial wall. In CAs, plaque thickness increased during atherogenesis. CAs showed compensatory enlargement (apoE(-/-) 55%, apoE*3-Leiden 38%). Regression analysis revealed a positive correlation between plaque and lumen area (for apoE(-/-), R=0.95; for apoE*3-Leiden, R=0.90). Medial thinning and elastolysis were also observed. During atherogenesis, lumen diameter decreased (apoE(-/-) -69%, apoE*3-Leiden -40%), and stenosis >70% developed. TA and AA showed similar features, but neither developed a progressive decrease in lumen diameter or stenosis >70%. In CAs, TA, and AA of apoE(-/-) and apoE*3-Leiden mice, atherogenesis is associated with compensatory enlargement, medial thinning, and elastolysis. A progressive decrease in lumen diameter and stenoses >70% occur only in CAs. Vascular remodeling is more prominent in apoE(-/-) mice.
 ...
PMID:Compensatory enlargement and stenosis develop in apoE(-/-) and apoE*3-Leiden transgenic mice. 1149 66

In the past, we believed that atherosclerosis gradually and progressively led to the complete occlusion of an artery, thereby causing acute coronary events. However, we now understand that rupture of a nonstenotic, yet vulnerable atherosclerotic plaque frequently leads to an acute coronary syndrome. Rupture-prone plaques typically have a thin fibrous cap, numerous inflammatory cells, a substantial lipid core, and surprisingly few smooth muscle cells. Physical disruption of such a plaque allows circulating blood coagulation factors to meet with the highly thrombogenic material in the plaque's lipid core, thereby instigating the formation of a potentially occluding and fatal thrombus. Much evidence implicates inflammation in the thinning of the fibrous cap and the disruption of the vulnerable atherosclerotic plaque. Lipid lowering undisputedly reduces the incidence of acute coronary events. However, the hypothesis that the mechanism of event reduction involves regression of fixed stenoses has proved untenable. In 14 angiographic studies, treatment of abnormal lipid levels increased luminal diameter only modestly, in stark contrast to the resounding and consistent decrease in acute coronary events produced by lipid lowering. Therefore, we now believe that lipid-lowering treatments, such as statins, modify plaques qualitatively as much as quantitatively, reducing inflammation and stabilizing noncritically stenotic, yet vulnerable plaques. Studies in rabbits with diet-induced atherosclerosis have shown that reducing cholesterol consumption indeed decreases inflammation in atheroma and improves those features of plaques associated with stability.
 ...
PMID:What have we learned about the biology of atherosclerosis? The role of inflammation. 1159 92

Clinical complications of atherosclerosis are often triggered by the rupture of unstable plaques, while thinning of the atherosclerotic vessel wall owing to elastin and collagen degradation and media necrosis may result in aneurysm formation and bleeding. Proteolysis, mediated via the plasminogen/plasmin and/or matrix metalloproteinase (MMP) systems may contribute to neovascularization and rupture of plaques, or to ulceration and rupture of aneurysms. In an in vivo model of atherosclerosis, using mice that had a combined deficiency of apolipoprotein E (ApoE) and urokinase-type plasminogen activator (u-PA) and that were maintained on a cholesterol-rich diet, it was observed that u-PA deficiency protects against aneurysm formation. This was explained by the findings that plasmin, generated from plasminogen by u-PA, activates several macrophage-secreted proMMPs (e.g. proMMP-3, -9, -12 and -13), which in turn cause extracellular matrix degradation. A potential role for MMP-3 (stromelysin-1) was confirmed in a subsequent study using mice with a combined deficiency of ApoE and MMP-3, that were kept on a cholesterol-rich diet. The results suggest that MMP-3 contributes to plaque destabilization, possibly by degrading extracellular matrix components, but also promotes aneurysm formation by degrading the elastic lamina. These effects may be mediated by MMP-3 directly or by activation of other proMMPs or other (proteolytic) systems. A functional role of MMPs is further supported by the finding that deficiency in TIMP-1 (tissue inhibitor of MMPs type 1) reduces atherosclerotic plaque size but enhances aneurysm formation. Taken together, these results suggest that u-PA has an important role in the structural integrity of the atherosclerotic vessel wall, which is likely to involve triggering the activation of MMPs and, furthermore, they suggest that increased u-PA levels are a risk factor for aneurysm formation.
 ...
PMID:Extracellular proteolysis in the development and progression of atherosclerosis. 1202 44

The RecQ family of DNA helicases have potential roles in DNA repair, replication and/or recombination pathways. In humans, a defect in the RecQ family helicases encoded by the BLM, WRN and RECQ4 genes gives rise to Bloom's (BS), Werner's (WS) and Rothmund-Thomson (RTS) syndromes, respectively. These disorders are associated with cancer predisposition and/or premature aging. In Bloom's syndrome, affected individuals are predisposed to many types of cancer at an early age. Werner's syndrome is a premature aging disorder with a complex phenotype, which includes many age-related disorders that develop from puberty, including greying and thinning of the hair, bilateral cataract formation, type II diabetes mellitus, osteoporosis and atherosclerosis. The phenotype of Rothmund-Thomson syndrome patients also consists of some features associated with premature aging, as well as predispositon to certain cancers. Here, we discuss the molecular basis of these RecQ helicase-deficient disorders.
 ...
PMID:Premature aging in RecQ helicase-deficient human syndromes. 1220 42

Most of the serious clinical manifestations (such as unstable angina, acute MI, and many cases of sudden death) of coronary atherosclerosis result from thrombosis, usually occurring on a disrupted atherosclerotic plaque. Plaques prone to disruption have large lipid-rich cores with evidence of cap-thinning and active inflammation. Inflammatory cells may contribute to both plaque disruption and subsequent thrombosis. Here we review the evidence for the involvement of inflammation in plaque disruption and thrombosis and the potential clinical implications of this pathophysiologic paradigm.
 ...
PMID:The role of inflammation in plaque disruption and thrombosis. 1243 85

Acute and chronic inflammation play a central role in the pathophysiology of atherosclerosis. Corticosteroids are the gold standard anti-inflammatory agent and may have a role in treating acute myocardial infarction. However, concern exists regarding the potential for impaired wound healing and wall thinning. The MEDLINE and PreMEDLINE databases were searched for articles from 1966 through May 2002. A total of 186 articles and 16 English-language publications were identified. A meta-analysis of mortality in controlled trials was performed. Sensitivity analyses and 2 tests for publication bias were used to test the robustness of the results. Sixteen studies involving 3,793 patients were reviewed. Most studies were small (<100 patients) and revealed conflicting efficacy using surrogate outcome measures, such as infarct size. No clear association with myocardial rupture was observed. Meta-analysis of 11 controlled trials (2,646 patients) revealed a 26% decrease in mortality with corticosteroids (odds ratio 0.74, 95% confidence interval [CI] 0.59 to 0.94; p = 0.015). Sensitivity analyses limited to large studies and randomized controlled trials revealed odds ratios of 0.76 (95% CI 0.53 to 1.09) and 0.95 (95% CI 0.72 to 1.26), respectively. Two tests revealed no evidence for publication bias. Thus, the review of available clinical studies demonstrated no harm and a possible mortality benefit of corticosteroids in acute myocardial infarction.
 ...
PMID:Meta-analysis of corticosteroid treatment in acute myocardial infarction. 1271 46

The materiel of intraoperative biopsies (378) and autopsies was used to study the morphology of the aortic wall in patients with Marfan's syndrome (62) and Erdheim's disease (133). Histological, histochemical and electron microscopy research methods were employed with an assay of the results obtained. It has been demonstrated that in connective tissue dysplasia in the aorta, the histological structure of the intima undergoes substantial changes alongside the pathology of the tunica media. It is marked by the formation of a focal and diffuse thickening with the predominance of the interstitial substance, rich in glycosaminoglycans, and of a small amount of fibrous structures. The morphological signs of the impairment of endothelial permeability (vacuolisation of cytoplasm, thinning of its peripheral portions and basal membrane, expansion of intercellular fissures) are identifiabe, which leads to the disorder of aortic wall metabolism and early development of atherosclerosis. The changes in the intima together with the pathology of the tunica media ere predisposing factors of aneurysm formation, dissection and rupture of the aorta.
 ...
PMID:A comparative study of the aortic wall in patients with Marfan's syndrome and Erdheim's disease. 1562 31

The arterial content of hyaluronan (HA) undergoes diffuse changes as part of the diabetic macroangiopathy. Because HA influences the phenotype of vascular cells in vitro such as proliferation, migration, and secretion, it is tempting to speculate that diabetes-induced hastened cardiovascular disease may be linked to the increased amount of HA. To explore the pathophysiological role of altered HA content in the arterial wall in vivo, we created transgenic (Tg) mice with HA overexpression in smooth muscle cells (SMCs) in large and small vessels, targeted by the alpha smooth-muscle-cell-actin (alphaSMA) promoter fused to the human hyaluronan synthase 2 (hHAS2) cDNA. RT-PCR demonstrated hHAS2 mRNA expression in the tunica media of large and small vessels. In situ hybridization confirmed that hHAS2 mRNA was targeted to the SMCs. The aortic HA content was elevated in the Tg mice, and by immunohistochemistry, it was seen that HA accumulated in the tunica media. The secretory profile of high- and low-molecular HA was similar in wild-type and Tg animals. Overproduction of HA in the aorta resulted in thinning of the elastic lamellae in Tg mice. Our data suggest that this may lead to increased mechanical stiffness and strength, as determined by controlled stretching until failure. Finally, overproduction of HA on the genetic background of the ApoE-deficient mouse strain promoted atherosclerosis development in the aorta. These results indicate that a single component of the diabetic macroangiopathy, diffuse accumulation of HA, accelerates the progression of atherosclerosis.
 ...
PMID:Overexpression of hyaluronan in the tunica media promotes the development of atherosclerosis. 1570 63


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