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)

Hyaluronate (HA), heparan sulfate (HS), dermatan sulfate (DS) and isomeric chondroitin sulfates (CS) were measured in vascular walls of 9-10 months old normal and hypophysectomized female beagles treated with sex hormones. Following hypophysectomy the animals were maintained for 8 weeks without any hormonal replacement therapy and then they were exposed for 3 weeks to parenteral treatment with sex hormones. One group received twice weekly 25 mg testosterone, another group was given the same amount of progesterone, and a third group received on day 1 and day 14, estrogens in 2 injections, consisting of a mixture of 10 mg short-acting estradiol-17-phenylpropionate and 2.5 mg long-acting estradiol benzoate. After 11 weeks all animals were sacrificed, coronary arteries and aortas were immediately removed and the latter were divided into three segments: arch, thoracic and abdominal. Removal of the pituitary led to a reduction of the HA content in the aortic arch and thoracic segment, but coronary arteries and abdominal aorta were not affected. The main consequence of hypophysectomy both in the entire aorta and in coronary arteries was a sharp reduction of the sulfated glycosaminoglycan (GAG) content. All three hormones produced a modest rise in the HS content of coronary arteries. A more definite response was seen in the thoracic aorta where each of the three hormones raised the low DS content to normal levels. Concerning the effect of sex hromones on aortic GAG other than DS, TESTOSTERONE RAISED THE CS content towards normal in thoracic and abdominal segments, while estrogen by doubling the normal HA concentration was particularly potent in the abdominal aorta. It is conceivable that the different sensitivity of various segments of aorta and coronary arteries to sex (and other) hormones in terms of regulating GAG metabolism may prove to be of relevance to the uneven distribution of lesions in degenerative vascular disease.
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PMID:The effect of sex hormones on glycosaminoglycan content of canine aorta and coronary arteries. 90 20

Experiments were designed to examine the effect of oxidized low density lipoproteins (Ox-LDLs) on the expression and the release of endothelin from cultured endothelial cells and intact blood vessels. Ox-LDLs (30-300 micrograms/ml), but not native low density lipoproteins (200 micrograms/ml), stimulated the expression of preproendothelin mRNA in porcine and human endothelial cells, leading to a time- and concentration-dependent release of the peptide into the culture medium. The Ox-LDL-stimulated release of endothelin was mimicked by acetylated low density lipoprotein and abolished by downregulation of protein kinase C by phorbol ester. In the intact porcine aorta, Ox-LDLs, but not native low density lipoproteins, also increased the release of peptide in an endothelium- and concentration-dependent manner. The maximal effect was observed at a concentration of 100 micrograms/ml. Incubation of the intact porcine aorta with the scavenger receptor antagonist dextran sulfate decreased the formation of endothelium evoked by Ox-LDLs. The Ox-LDL-stimulated production of the peptide was further augmented in the presence of thrombin (4 units/ml) and was unaffected by nitric oxide-generating compound 3-morpholinosydnonimine (10(-5) M). These results suggest that Ox-LDL may be an endogenous mediator of the augmented release of endothelin observed in hyperlipidemia and atherosclerosis. The increased production of the peptide could contribute to vasospastic events and may promote vascular smooth muscle proliferation and progression of atherosclerotic vascular disease.
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PMID:Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium. 131 34

Impaired elastin fiber assembly is observed in the fetal ductus arteriosus (DA), associated with a reduced concentration of elastin binding protein (EBP), a 67-kDa galactolectin. It is also seen in cultured aortic (Ao) smooth muscle cells (SMC) following the release of the EBP by glycosaminoglycans rich in N-acetylgalactosamine, such as chondroitin sulfate (CS). In the DA, impaired elastin fiber assembly is observed in conjunction with intimal thickening associated with increased migration of SMC into the subendothelium, a feature we previously related to increased production of fibronectin. In this report, we determined whether SMC use the EBP to attach to an elastin substrate, whether shedding of the EBP promotes SMC migration through a three-dimensional network of pure elastic laminae prepared from sheep aorta, and whether the latter is associated with increased production of fibronectin. We observed reduced attachment to elastin-coated surfaces of DA SMC deficient in EBP compared to Ao SMC. Addition of CS but not heparan sulfate (a glycosaminoglycan which does not induce EBP shedding) decreased Ao SMC attachment to elastin, as did preincubation with VGVAPG elastin-derived peptides which saturate the EBP. The immunolocalization of cell surface EBP suggested that cells can quickly replace EBP released from their surfaces by CS treatment. The magnitude of CS-induced impaired attachment of SMC to elastin was dose dependent and could be further increased by the administration of cyclohexamide and sodium azide. Also, the reversibility of CS-induced detachment was prevented by monensin. This suggests that a process of new synthesis and intracellular transport of the EBP was necessary to replace the EBP molecules released from the cell surface by CS treatment. In the migration assay, both DA and Ao SMC attached to the top of an elastin membrane, but only DA SMC deficient in EBP migrated through the laminae. Addition of CS, which induced shedding of EBP, resulted in Ao SMC migration associated with increased synthesis of fibronectin. We postulate that CS-induced release of EBP from SMC surfaces causes cell detachment from elastin and an increase in fibronectin synthesis, processes which may be critical in promoting SMC migration associated with intimal thickening developmentally in the DA and perhaps also in vascular disease.
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PMID:Vascular smooth muscle cell detachment from elastin and migration through elastic laminae is promoted by chondroitin sulfate-induced "shedding" of the 67-kDa cell surface elastin binding protein. 133 80

Diabetes is accompanied by impaired platelet function and accelerated vascular disease. To find out whether a correlation exists between these two complications, and if modifications occurring in diabetic platelets influence their relationship with endothelium, we have studied the interaction between platelets isolated from plasma of diabetic patients and bovine valvular endothelial cells (VEC), in culture. For quantitative analysis, normal and diabetic [3H]-adenine-labeled platelets were incubated with confluent VEC grown in Dulbecco's modified Eagle medium, containing 4.5 g/l glucose, for 30 min at 37 degrees C. After extensive washing and solubilization of the monolayer, the calculated adhesion index showed a two-fold increased adherence of diabetic platelets to VEC as compared to normal platelets. Statistical analysis (by Pitman randomization test) indicated that the adhesion was significantly higher (p = 0.0003) than that of normal platelets to VEC. To partially identify the membrane components implicated in the adhesion process, either platelets or VEC were treated with neuraminidase, trypsin or heparinase prior to the adhesion assay. Trypsin or neuraminidase treatment of platelets significantly diminished their adherence to VEC, suggesting a role of platelets sialylated glycoproteins in the adhesion process. Neuraminidase or heparinase treatment of VEC increased the adhesion of both normal and diabetic platelets, indicating that the cell membrane sialyl residues and heparan sulfate participate in the normal thromboresistant properties of VEC. Transmission and scanning electron microscopy revealed a close apposition between platelets and VEC with the formation of an adhesion plaque, characterized by fine fibrillar bridges between the plasma membranes of the two cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased adhesion of human diabetic platelets to cultured valvular endothelial cells. 145 40

Pulmonary vascular disease (PVD) revolves around a series of switches in the smooth muscle cell (SMC) phenotype. Differentiation of SMC from precursor cells causes muscularization of normally non-muscular peripheral arteries; hypertrophy and hyperplasia of existing SMC and increased connective tissue protein synthesis cause thickening of the wall, and migration of SMC into the subendothelial space is the basis of intimal proliferation. To uncover the pathophysiologic mechanisms of these changes, we have used a variety of animal models and cell culture systems. From rats in which hypertensive PVD was induced by exposure to chronic hypoxia or following injection of the pyrrolizidine alkaloid, monocrotaline, we have identified increased pulmonary artery (PA) elastolytic activity which occurs early and which accompanies progressive rather than reversible PVD. Inhibition of elastolytic activity prevents or reduces PVD. We are cloning the gene for this new enzyme to study its regulation in PVD. To address the mechanism of SMC proliferation under conditions of high PA pressure and flow, we cultured endothelial cells on polyvinylchloride membranes and pulsated them at high pressure. This caused reduced synthesis of heparan sulfate. The resulting decrease binding of fibroblast growth factor would lessen its mitogenic effect and modulate SMC proliferation in response to other growth factors from platelets or serum. To study SMC migration, we cultured endothelial and SMC from the ductus arteriosus (a fetal vessel which spontaneously develops intimal proliferation in late gestation). The migratory SMC phenotype is a function of increased production of fibronectin governed by a translational control mechanism, and increased endothelial hyaluronan regulated by transforming growth factor beta. SMC migration is also related to impaired assembly of elastin, the result of a chondroitin sulfate-induced decrease in elastin binding proteins and the production of a novel 'defunct' 52 kD tropoelastin.
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PMID:Investigational approaches to pulmonary hypertension. 181 89

Increasing evidence suggests that the formation of oxidized low-density lipoprotein (Ox-LDL) in vivo is associated with the development of atherosclerotic vascular disease. We investigated the effects of Ox-LDL on two vascular endothelial cell coagulant properties, tissue factor expression, and protein C activation. The Ox-LDL increased human arterial and venous endothelial cell tissue factor activity, with 100 micrograms/ml of Ox-LDL increasing factor activity fourfold. Native LDL modified by incubation with cultured human arterial and venous endothelial cells also induced endothelial cell tissue factor activity. This modification was blocked by coincubation with the antioxidants, probucol or ascorbic acid. It was determined, based on inhibition by known scavenger receptor antagonists (fucoidin, dextran sulfate), that binding of Ox-LDL via the acetyl LDL (scavenger) receptor was partially responsible for the increase in tissue factor expression. Whereas endothelial cell tissue factor expression was increased by incubation with Ox-LDL, protein C activation was reduced approximately 80% by incubating cultured endothelial cells with Ox-LDL. The effect of Ox-LDL on protein C activation was not inhibited by antagonists to the scavenger receptor. These data indicating that an atherogenic lipoprotein can regulate key vascular coagulant activities provide an additional link between vascular disease and thrombosis.
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PMID:Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation. 206 93

A monoclonal antibody (HK-249) that recognizes a glucosamine sulfate alpha 1----4 glucuronic acid-containing determinant in heparan sulfate (HS) chains of a basement membrane-derived heparan sulfate proteoglycan identified and immunolocalized HS specifically to the amyloid deposits in neuritic plaques (NPs), congophilic angiopathy (CA), as well as in neurofibrillary tangles (NFTs) and non-tangle-bearing neurons in the brains of Alzheimer's and Down's syndrome (DS) patients. Ultrastructural immunohistochemistry demonstrated that HS within neurons of Alzheimer's disease (AD) brain was localized to lipofuscin granules, an aging pigment previously shown also to contain beta-amyloid protein (BAP). Heparan sulfate also was localized to neurite-containing, nonfibrillar 'primitive' plaques that also demonstrated positive BAP immunoreactivity in both AD and DS brains. Antibodies to laminin, fibronectin, and a chondroitin sulfate proteoglycan failed to show positive immunostaining of the HS-containing sites described above. Analysis of DS patients at different ages revealed that HS accumulated within neurons of the hippocampus and amygdala as early as 1 day after birth. Young age-matched controls did not demonstrate similar positive HS immunoreactivity in neurons, whereas positive immunostaining for HS was observed in other regions thought to normally contain HS. The earliest deposition of BAP was first observed as 'amorphous' or 'diffuse' cortical deposits in DS brain in patients aged 18 and 24 years before the accumulation of fibrillar amyloid (observed in DS patients who are 35 years and older). These cortical deposits also contained positive HS immunoreactivity, implying that HS accumulation in conjunction with the BAP is an early event that ultimately may contribute to the early age-related accumulation (ie, as early as 35 years of age in DS) of NPs, NFTs, and/or CA. Furthermore the colocalization of HS and BAP in a number of specific locales in AD and DS brain indicates a possible interaction between these two macromolecules that may be important in lesion development in these two diseases.
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PMID:Early accumulation of heparan sulfate in neurons and in the beta-amyloid protein-containing lesions of Alzheimer's disease and Down's syndrome. 214 82

In the present investigation, we analyzed whether sulfated glycosaminoglycans are a common constituent in many different types of amyloid. Serial sections of amyloidotic tissue were stained for the presence of: (a) amyloid by using Congo Red, and (b) glycosaminoglycans by using both the sodium sulfate Alcian blue method and Alcian blue, pH 5.7, with varying concentrations of magnesium chloride. Our results show that sulfated glycosaminoglycans are always associated anatomically with amyloid deposits regardless of the nature of the protein deposited. Sulfated glycosaminoglycans were found in tissues containing AA, AL, inherited cutaneous amyloid, and senile cardiac amyloid (prealbumin). Additionally, we provide evidence that sulfated glycosaminoglycans are closely associated with the amyloid of medullary carcinoma of the thyroid (prothyrocalcitonin), and neuritic plaques, neurofibrillary tangles, and congophilic angiopathy in Alzheimer's disease. It is postulated that these sulfated glycosaminoglycans can influence the folding of diverse proteins such that all forms of amyloid show a significant beta-pleated sheet component.
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PMID:Sulfated glycosaminoglycans: a common constituent of all amyloids? 243 52

The authors of this article present and attempt to substantiate the thesis that proteoglycan(s), mainly heparan sulfate, are an important ingredient in the pathogenesis of the amyloid found in persons with Alzheimer's disease. Evidence presented indicates that glycosaminoglycans are regular constituents of many amyloid substances including that of senile plaques and congophilic angiopathy of Alzheimer's disease. It is proposed that the proteoglycans play a role in amyloidogenesis by one or a combination of the following mechanisms: 1) inducing amyloid fibrils containing a predominant beta-pleated sheet structure, 2) influencing amyloid deposition to occur at specific tissue sites and/or 3) prevent amyloid degradation.
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PMID:What role(s) may extracellular matrix, particularly heparan sulfate, play in amyloid of Alzheimer's disease. 253 Apr 63

In 1949, amphetamine sulfate was replaced by propylhexedrine in the nasal decongestant agent Benzedrex because of psychosis, sudden death, and widespread abuse. Propylhexedrine is not without risks, and reported cases of psychosis, myocardial infarction, pulmonary vascular disease and pulmonary hypertension, and sudden death are well documented in the medical literature. We are reporting 2 cases of definite brainstem dysfunction and 5 cases of transient diplopia secondary to IV abuse of Benzedrex. This widely abused drug is prepared by heating Benzedrex and hydrochloric acid, and the resulting crystals are dissolved in water for injection. This agent is called "stove-top speed". All 7 patients had transient diplopia, within seconds after injection. One patient had evidence of a right-internuclear ophthalmoplegia, and another had a depressed right gag reflex and paralysis of the right half of the tongue. The deficits in these two patients, persisted for many months. In young adults with history of drug abuse, the IV use of Benzedrex should be considered in the differential diagnosis of transient or permanent focal brainstem deficits.
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PMID:Intravenous abuse of propylhexedrine (Benzedrex) and the risk of brainstem dysfunction in young adults. 287 25


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