Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitronectin (Vn) regulates proteolytic enzyme systems, as well as cell migration and tissue remodelling. These processes have been implicated in the pathogenesis of atherosclerosis. In this study, the distribution of Vn antigen in apparently normal and atherosclerotic human blood vessels was evaluated. Normal and diseased vessels showed Vn immunostaining in the lamina elastica interna and externa, and in strand-like structures in the adventitia. In most of these instances, the Vn antigen appeared to be located in the proximity of elastin. In pulmonary arteries, Vn staining was additionally detected in the media. The intima was devoid of Vn antigen in all vessels studied. In general, there was increased deposition of Vn antigen in the atherosclerotic arteries. In particular, strong Vn staining was apparent in amorphous material adjacent to cholesterol clefts and in acellular fibrous tissue, in plaques present in the carotic artery and aorta. Collagen layers and fresh fibrin depositions were devoid of Vn antigen. In spite of the abundance of Vn immunostaining throughout the normal and diseased vessel wall, the Vn transcript was not detectably by in situ hybridization. These results indicate that Vn is a constituent of the normal vessel wall and raise the possibility that increased local deposition of Vn may be related to the development of atherosclerotic vascular disease.
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PMID:Localization of vitronectin in the normal and atherosclerotic human vessel wall. 915 Nov 13

Aortic aneurysm and dissection account for about 2% of all deaths in industrialized countries; they are also components of several genetic diseases, including Marfan syndrome (MFS). The vascular phenotype of MFS results from mutations in fibrillin-1 (FBN1), the major constituent of extracellular microfibrils. Microfibrils, either associated with or devoid of elastin, give rise to a variety of extracellular networks in elastic and non-elastic tissues. It is believed that microfibrils regulate elastic fibre formation by guiding tropo-elastin deposition during embryogenesis and early post-natal life. Hence, vascular disease in MFS is thought to result when FBN1 mutations preclude elastic fibre maturation by disrupting microfibrillar assembly. Here we report a gene-targetting experiment in mice that indicates that fibrillin-1 microfibrils are predominantly engaged in tissue homeostasis rather than elastic matrix assembly. This finding, in turn, suggests that aortic dilation is due primarily to the failure by the microfibrillar array of the adventitia to sustain physiological haemodynamic stress, and that disruption of the elastic network of the media is a secondary event.
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PMID:Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. 932 47

Arterial wall stresses are thought to be a major determinant of vascular remodeling both during normal growth and throughout the development of occlusive vascular disease. A completely physiologic mechanical model of the arterial wall should account not only for its residual strains but also for its structural nonhomogeneity. It is known that each layer of the artery wall possesses different mechanical properties, but the distribution of residual strain among the different mechanical components, and thus the true zero stress state, remain unknown. In this study, two different sets of experiments were carried out in order to determine the distribution of residual strains in artery walls, and thus the true zero stress state. In the first, collagen and elastin were selectively eliminated by chemical methods and smooth muscle cells were destroyed by freezing. Dissolving elastin provoked a decrease in the opening angle, while dissolving collagen and destroying smooth muscle cells had no effect. In the second, different wall layers of bovine carotid arteries were removed from the exterior or luminal surfaces by lathing or drilling frozen specimens, and then allowing the frozen material to thaw before measuring residual strain. Lathing material away from the outer surface caused the opening angle of the remaining inner layers to increase. Drilling material from the inside caused the opening angle of the remaining outer layers to decrease. Mechanical nonhomogeneity, including the distribution of residual strains, should thus be considered as an important factor in determining the distribution of stress in the artery wall and the configuration of the true zero stress state.
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PMID:Experimental investigation of the distribution of residual strains in the artery wall. 940 83

Supravalvular aortic stenosis (SVAS) occurs as an autosomal dominant trait or as part of the phenotype of the usually sporadic condition Williams syndrome. SVAS is the result of mutation or deletion of the elastin gene (ELN), located at chromosome 7q11.23. Thus, SVAS may be more appropriately termed an elastin arteriopathy. Studies have demonstrated various point mutations and intragenic deletions of ELN resulting in nonsyndromic SVAS. Individuals with Williams syndrome are hemizygous for the elastin gene, owing to a 1 to 2 megabase deletion of a portion of the long arm of chromosome 7 that encompasses ELN. This submicroscopic deletion is readily detected by fluorescent in-situ hybridization, useful in the diagnosis of Williams syndrome. The severity of SVAS is quite variable, both in series of Williams syndrome patients and within SVAS kindreds, suggesting that other genetic factors are involved in expression of the phenotype. Experiments with elastin knockout mice will likely yield clues regarding the role of elastin in arterial morphogenesis and the pathogenesis of obstructive vascular disease.
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PMID:Genetic aspects of supravalvular aortic stenosis. 964 45

Obstructive vascular disease is an important health problem in the industrialized world. Through a series of molecular genetic studies, we demonstrated that loss-of-function mutations in one elastin allele cause an inherited obstructive arterial disease, supravalvular aortic stenosis (SVAS). To define the mechanism of elastin's effect, we generated mice hemizygous for the elastin gene (ELN +/-). Although ELN mRNA and protein were reduced by 50% in ELN +/- mice, arterial compliance at physiologic pressures was nearly normal. This discrepancy was explained by a paradoxical increase of 35% in the number of elastic lamellae and smooth muscle in ELN +/- arteries. Examination of humans with ELN hemizygosity revealed a 2. 5-fold increase in elastic lamellae and smooth muscle. Thus, ELN hemizygosity in mice and humans induces a compensatory increase in the number of rings of elastic lamellae and smooth muscle during arterial development. Humans are exquisitely sensitive to reduced ELN expression, developing profound arterial thickening and markedly increased risk of obstructive vascular disease.
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PMID:Novel arterial pathology in mice and humans hemizygous for elastin. 981 63

Increased elastase activity and deposition of the matrix glycoprotein tenascin-C (TN), codistributing with proliferating smooth muscle cells (SMCs), are features of pulmonary vascular disease. In pulmonary artery (PA) SMC cultures, TN is regulated by matrix metalloproteinases (MMPs) and mechanical stress. On attached collagen gels, MMPs upregulate TN, leading to SMC proliferation, whereas on floating collagen, reduced MMPs suppress TN and induce SMC apoptosis. We now investigate the response of SMCs in the whole vessel by comparing attached and floating conditions using either normal PAs derived from juvenile pigs or normal or hypertrophied rat PAs that were embedded in collagen gels for 8 days. Normal porcine PAs in attached collagen gels were characterized by increasing activity of MMP-2 and MMP-9 assessed by zymography and TN deposition detected by Western immunoblotting and densitometric analysis of immunoreactivity. PAs on floating collagen showed reduced activity of both MMPs and deposition of TN. Tenascin-rich foci were associated with proliferating cell nuclear antigen immunoreactivity, and TN-poor areas with apoptosis, by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, but no difference in wall thickness was observed. Although normal rat PAs were similar to piglet vessels, hypertrophied rat PAs showed an amplified response. Increased elastase, MMP-2, TN, and elastin deposition, as well as SMC proliferating cell nuclear antigen positivity, correlated with progressive medial thickening on attached collagen, whereas reduced MMP-2, elastase, TN, and induction of SMC apoptosis accompanied regression of the thickened media on floating collagen. In showing that hypertrophied SMCs in the intact vessel can be made to apoptose and that resorption of extracellular matrix can be achieved by inhibition of elastase and MMPs, our study suggests novel strategies to reverse vascular disease.
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PMID:Regression of hypertrophied rat pulmonary arteries in organ culture is associated with suppression of proteolytic activity, inhibition of tenascin-C, and smooth muscle cell apoptosis. 1034 97

The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, but whether endogenous local inhibitors counterbalance these proteases is unknown. We show here that, whereas cystatin C is normally expressed in vascular wall smooth muscle cells (SMCs), this cysteine protease inhibitor is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Furthermore, increased abdominal aortic diameter among 122 patients screened by ultrasonography correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular SMCs secrete cathepsins, whose elastolytic activity could be blocked when cystatin C secretion was induced by treatment with TGF-beta(1). The findings highlight a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and establish that cystatin C deficiency occurs in vascular disease.
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PMID:Cystatin C deficiency in human atherosclerosis and aortic aneurysms. 1054 13

Nitric oxide (NO) reduces the severity of pulmonary vascular disease in rats as do elastase inhibitors. We therefore hypothesized that NO inhibits elastase by suppressing mitogen-activated protein kinases that trans-activate AML1B, a transcription factor for elastase. We used cultured pulmonary artery smooth muscle cells in which serum-treated elastin (STE) induces a > threefold increase in elastase activity as evaluated by solubilization of [(3)H]-elastin. NO donors (SNAP and DETA NONOate) inhibited elastase in a dose-dependent manner as did a cGMP mimetic (8-pCPT-cGMP). SNAP inhibition of elastase was reversed by coadministration of a cGMP-PKG inhibitor (Rp-8-pCPT-cGMP). The STE-induced increase in phospho-ERK was suppressed by NO donors and the cGMP mimetic, and reversed by cGMP-PKG inhibitor, as was expression of AML1B and DNA binding in nuclear extracts. A concomitant increase in p38 phosphorylation was also inhibited by SNAP, but whereas MEK inhibitor (PD98059) suppressed elastase and AML1B-DNA binding, a p38 inhibitor (SB202190) did not. Our study uniquely links NO with inhibition of elastase-dependent matrix remodeling in vascular disease by suggesting a cGMP-PKG-related mechanism suppressing ERK-mediated partitioning of AML1B in nuclear extracts.
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PMID:Nitric oxide reduces vascular smooth muscle cell elastase activity through cGMP-mediated suppression of ERK phosphorylation and AML1B nuclear partitioning. 1074 37

Progression of pulmonary hypertension is associated with increased serine elastase activity and the proteinase-dependent deposition of the extracellular matrix smooth muscle cell survival factor tenascin-C (refs. 1,2). Tenascin-C amplifies the response of smooth muscle cells to growth factors, which are also liberated through matrix proteolysis. Recent organ culture studies using hypertrophied rat pulmonary arteries have shown that elastase inhibitors suppress tenascin-C and induce smooth muscle cell apoptosis. This initiates complete regression of the hypertrophied vessel wall by a coordinated loss of cellularity and extracellular matrix. We now report that elastase inhibitors can reverse advanced pulmonary vascular disease produced in rats by injecting monocrotaline, an endothelial toxin. We began oral administration of the peptidyl trifluoromethylketone serine elastase inhibitors M249314 or ZD0892 21 days after injection of monocrotaline. A 1-week treatment resulted in 92% survival, compared with 39% survival in untreated or vehicle-treated rats. Pulmonary artery pressure and muscularization were reduced by myocyte apoptosis and loss of extracellular matrix, specifically elastin and tenascin-C. After 2 weeks, pulmonary artery pressure and structure normalized, and survival was 86%, compared with 0% in untreated or vehicle-treated rats. Although concomitant treatment with various agents can reduce pulmonary hypertension, we have documented complete regression after establishment of malignant monocrotaline-induced disease.
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PMID:Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. 1083 89

In a longitudinal clinical study, two hundred subjects have been evaluated in order to identify alpha 1-antitrypsin deficiency patients. According to their serum alpha 1-antitrypsin levels, they have been divided into three groups: 25 patients with severe deficiency (with both pathological alleles--ZZ, SZ or Z and rare deficiency allele--and, if clinically suggested, to be treated with augmentation therapy), 92 patients with intermediate deficiency (with one pathological allele, to be followed up in order to evaluate the risk to develop deficiency related disease) and 63 healthy subjects (normal alleles MM). They performed lung function test (including cardiopulmonary exercise test and methacholine bronchial challenge) chest X-ray and high resolution computed tomography, blood tests. Severe deficiency patients also performed perfusional lung scan to detect early disorders of blood flow, evaluation of arterial blood gases and liver echotomography. Expiratory flow limitation, the prevalence of vascular disease, the amount of urine elastin products and correlations between the amount of nitric oxide exhaled and bronchial hyperresponsiveness have been also investigated. The study showed that in Brescia county the deficiency is more common than expected and that evaluation of liver and vessels might be as useful as lung function tests. In addition, beneficial effect on local system has been observed. The longitudinal study might permit to detect early organ damage and to eliminate additive risk factors.
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PMID:[Alpha 1-antitrypsin deficiency: the Brescia clinical study]. 1093 19


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