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)

To investigate the effects of hyperinsulinemia on the myocardial vessels, long acting insulin (mixtard, a combination of 30% regular human insulin and 70% NPH human insulin) was injected daily for 8 weeks, intraperitoneally, in two strains of rats, normotensive WKY and hypertensive SHR. There were four groups in all, a control group, and an insulin-injected group in each strain. The drinking water contained 10% glucose to prevent hypoglycemia in the insulin-injected rats. At the end of the 8 weeks experimental period, after measuring blood pressure and taking blood for the determination of glucose, urea, creatinine, and insulin, the rats were killed. The organs were fixed in formaldehyde. The blood glucose levels were higher at the end of the experiment, in both the placebo- (saline)-injected and the insulin-injected rats. Blood pressure rose significantly only in the insulin-injected SHR. The intramyocardial arterioles in the insulin-injected SHR had a significantly thicker vascular wall than the placebo-injected SHR, as represented by the vessel wall to lumen ratio, because of hypertrophy of the media. When compared with the placebo injected WKY rats, there was a higher wall/lumen ratio of the intramyocardial arterioles in the insulin-injected WKY, but the difference did not reach significance. Heart weights factored by body weights was significantly higher in insulin-injected as compared with placebo-injected SHR. Myocardial infarctions were observed in four of eight rats in the insulin-injected SHR group despite the fact that there were no signs of atherosclerosis or intimal thickening. It is possible that the increase in heart weight and the probable increase in metabolic activity resulting from hyperinsulinemia, together with the increased oxygen demand of the myocardium and the arteriolar narrowing, may have contributed to the occurence of myocardial infarctions in the absence of atherosclerotic coronary occlusion.
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PMID:Hyperinsulinemia induces myocardial infarctions and arteriolar medial hypertrophy in spontaneously hypertensive rats. 919 11

The mouse is known to be highly resistant to atherosclerosis. However, some inbred mouse strains are vulnerable to atherosclerosis when they are fed a high-cholesterol, high-fat diet. Increased deamination of methylamine (MA) and the subsequent production of formaldehyde has been recently shown to be a potential risk factor of atherosclerosis. In the present study semicarbazide-sensitive amine oxidase (SSAO)-mediated MA turnover in C57BL/6 mouse, a strain very susceptible to atherosclerosis, has been assessed in comparison to a moderate, i.e. BALB/c, and resistant, i.e. CD1, mouse strains. Kidney and aorta SSAO activities were found to be significantly increased in C57BL/6 in comparison to BALB/c and CD1 mice. A significant increase of urinary MA and formaldehyde were detected in C57BL/6. [14C]MA following intravenous injection would be quickly metabolized by SSAO. The labeled formaldehyde product would cross link with proteins. C57BL/6 exhibits significantly higher labeled protein adducts than BALB/c and CD1 in response to [14C]MA. The results indicated that mice vulnerable to atherosclerosis possess an increased SSAO-mediated MA turnover. The increase of production of formaldehyde, possibly other aldehydes, may induce endothelial injury or be chronically involved in protein cross-linking and subsequent angiopathy.
Atherosclerosis 1998 Oct
PMID:Endogenous formaldehyde as a potential factor of vulnerability of atherosclerosis: involvement of semicarbazide-sensitive amine oxidase-mediated methylamine turnover. 986 79

Semicarbazide-sensitive amine oxidase (SSAO) is present in the plasma membrane of several human tissues, e.g. vascular smooth muscle cell adipocytes, and is also found in human serum. Some previous studies on cultured endothelial cells indicate that cytotoxic metabolites (e.g. hydrogen peroxide, formaldehyde, acrolein) formed by serum SSAO may cause endothelial injury and subsequently induce atherosclerosis. To investigate the role of this enzyme in the pathogenesis of macrovascular complications in diabetes, a simple and sensitive radiometric procedure was adapted for human serum measurements. Serum SSAO activity of 35 patients with non-insulin dependent diabetes mellitus (NIDDM) and that of 30 controls was determined using [14C]-benzylamine as substrate. The severity of atherosclerosis was assessed by carotid sonography. Diabetic patients with atherosclerosis exhibited a higher SSAO activity compared to diabetic patients without complications (212.91 +/- 90.54 pmol/mg protein/h versus 133.17 +/- 65.40 pmol/mg protein/h, P <0.04). In diabetic patients without complications, serum SSAO activity was elevated compared to control subjects (133.17 +/- 65.40 pmol/mg protein/h versus 91.79 +/- 31.70 pmol/mg protein/h, P <0.01). These results suggest that determination of human serum SSAO activity might be a useful marker in the prognostic evaluation of diabetic angiopathy and atherosclerosis.
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PMID:Determination of human serum semicarbazide-sensitive amine oxidase activity: a possible clinical marker of atherosclerosis. 1089 91

Recent data suggest that elevated serum semicarbazide-sensitive amine oxidase activity (SSAO) may cause endothelial injury. Formation of cytotoxic metabolites (especially formaldehyde) and increased oxidative stress might lead to initiation or progression of atherosclerosis. Effective and selective inhibitors of human SSAO might exert cytoprotective effect on endothelial cells. To compare the inhibitor sensitivity of human serum and vascular tissue SSAO enzyme, the inhibitory effect of semicarbazide and MDL 72974A was investigated. Serum and vascular SSAO activity has been determined using 14C-benzylamine as a substrate. The IC50 values of semicarbazide were estimated to be 5x10(-3) M and 5x10(-4) M for SSAO from human serum and saphenous vein, respectively. MDL 72974A amine oxidase inhibitor was more than thousand times more effective than semicarbazide. The IC50 values were 10(-7) M and 10(-8) M for SSAO from human serum and saphenous vein, respectively. This finding supports the hypothesis that soluble and membrane-bound vascular SSAO enzymes might have similar structure.
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PMID:Inhibitor sensitivity of human serum and vascular semicarbazide-sensitive amine oxidases. 1106 Dec 16

A synthetic heparin-mimicking polyaromatic anionic compound RG-13577 (polymer of 4-hydroxyphenoxy acetic acid and formaldehyde ammonium salt, Mr approximately 5800) exhibits specific binding to vascular smooth muscle cells (SMCs) and inhibits their proliferative response to growth promoting factors. Receptor binding of (14)C-RG-13577 was efficiently competed by apolipoprotein E3 (apoE), lactoferrin, and the LRP (LDL receptor-related protein) receptor associated 39 kDa protein (RAP). Unlike cell surface binding of apoE, binding of RG-13577 to SMCs was not affected by heparin, heparan sulfate degrading enzymes, or low density lipoprotein (LDL). Moreover, wild-type and heparan sulfate-deficient Chinese hamster ovary (CHO) cells, as well as normal- and LDL receptor negative- human skin fibroblasts bind RG-13577, but not apoE, to a similar extent. On the other hand, homozygous mouse embryonic fibroblasts deficient in the LDL receptor-related protein (LRP) expressed a markedly reduced binding of RG-13577 as compared to normal mouse embryonic fibroblasts. These results indicate that RG-13577 and related compounds bind to the LRP receptor on the surface of vascular SMCs. Addition of lactoferrin to cultured SMCs protected the cells against the antiproliferative effect of compound RG-13577, suggesting that this inhibition is mediated by RG-13577 binding to LRP receptors on the SMC surface. Altogether, we have identified a series of synthetic polyaromatic anionic molecules that exhibit specific binding to LRP and thereby exert an antiproliferative effect on vascular SMCs. These compounds are applied to suppress SMC proliferation associated with restenosis and accelerated atherosclerosis.
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PMID:A synthetic heparin-mimicking polyanionic compound binds to the LDL receptor-related protein and inhibits vascular smooth muscle cell proliferation. 1118 Apr 2

Quantifying the severity of adrenocortical nodular hyperplasia at autopsy or surgery has much potential practical value. For instance, this inquiry explores the correlation of adrenal nodularity with features of atherosclerosis in coronary arteries and microvascular features of hypertension in the renal cortex. Tissue retrieved from forensic autopsies in 96 men and women ages 16 to 88 years were evaluated for adrenal nodularity, coronary atheroma, and hypertensive renal microvasculopathies. Formalin-fixed adrenal glands were cut into 0.5-cm thick slices and fixed to plastic sheets with SuperGlue (Ross Products, Inc, Columbus, OH). After ranking the specimens on increasing nodularity, they were judged to fall into 10 distinguishable grades of increasing severity; photographs of a representative in each grade were arranged onto a panel. Each gland was then assigned the grade of the photograph it most resembled. Coronaries and kidneys were evaluated in paraffin sections. Weight and nodularity of adrenal glands increased with age. Men with at least one instance of atheroma in the coronary sample had heavier and more nodular glands (age-adjusted) than in men without atheroma. The differences held stronger statistical significance for nodularity than for weight because nodularity continued to show significance even within age groups sometimes represented by few cases. Hypertensive renal microvasculopathies failed to correlate with any of the adrenal features. Women were too few for the analysis. Findings made with the panel of photographs now available for grading adrenocortical nodular hyperplasia showed interesting correlations with coronary atherosclerosis in this data set, suggesting that use of this method might offer some insight into cardiovascular disease.
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PMID:A method for quantifying adrenocortical nodular hyperplasia at autopsy: some use of the method in illuminating hypertension and atherosclerosis. 1184 76

Apoptosis of intimal cells is an important contributor to the pathogenesis of atherosclerosis and transplant vascular disease (TVD). Since the activated immune response may be a key regulator of apoptosis in these lesions, we used immunohistochemistry to characterize the presence and localization of granzyme B, a major mediator of the cytotoxic immune response, in advanced atherosclerosis and TVD. Formalin-fixed, paraffin-embedded transverse sections from human left anterior descending coronary arteries were cut serially and stained with antibodies specific for granzyme B, smooth muscle alpha-actin, CD68, and CD3. The amount of granzyme B staining was semi-quantitated on a 0-5+/5+ scale. Also, TUNEL staining and in situ hybridization was performed to visualize cells undergoing cellular damage suggestive of apoptosis, and to localize granzyme B mRNA, respectively. Granzyme B localization was similar in both diseases. This protease was absent in arteries with mild atherosclerosis, but was abundant in the intima and media of vessels with advanced atherosclerosis and TVD. Within the intima, granzyme B localized to TUNEL-positive foam cells surrounding lipid-rich atheromas. Staining of serial sections with granzyme B and either smooth muscle alpha-actin, anti-CD68, or anti-CD3 showed that granzyme B localized to smooth muscle cells, macrophages, and T-cells. Further, in situ hybridization for granzyme B mRNA in TVD cases localized its expression to infiltrating leukocytes and not foam cells. In conclusion, the presence of granzyme B in advanced atherosclerotic lesions and TVD is associated with increasing disease severity and cell death. These observations suggest that granzyme B-mediated apoptosis may contribute to the pathogenesis of these diseases.
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PMID:Granzyme B in atherosclerosis and transplant vascular disease: association with cell death and atherosclerotic disease severity. 1274 53

Causative molecular mechanisms accounting for the potential link between Chlamydia pneumoniae and atherosclerosis are unknown. Formalin and heat-inactivated C. pneumoniae activated the transcription factor nuclear factor (NF)-kappaB in cultured porcine endothelium and up-regulated the expression of E-selectin messenger RNA and protein. This up-regulation was abolished by an IkappaB super-repressor, an NF-kappaB-specific inhibitor. Live bacteria are not necessary for the activation of endothelial NF-kappaB, and C. pneumoniae may contribute to atherogenesis without active infection.
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PMID:Nuclear factor-kappaB activation in endothelium by Chlamydia pneumoniae without active infection. 1455 77

Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the conversion of methylamine to formaldehyde. This enzyme is located on the surface of the cytoplasmic membrane and in the cytosol of vascular endothelial cells, smooth muscle cells, and adipocytes. Increased SSAO activity has been found in patients with diabetes mellitus, chronic heart failure, and multiple types of cerebral infarcts and is associated with obesity. Increased SSAO-mediated deamination may contribute to protein deposition, the formation of plaques, and inflammation, and thus may be involved in the pathophysiology of chronic vascular and neurological disorders, such as diabetic complications, atherosclerosis, and Alzheimer's disease. In the present study, we demonstrate the induction of cross-linkage of formaldehyde with the lysine moiety of peptides and proteins. Formaldehyde-protein adducts were reduced with sodium cyanoborohydride, hydrolyzed in hydrochloric acid, and the amino acids in the hydrolysates were derivatized with fluorenylmethyl chloroformate and then identified with high-performance liquid chromatography. We further demonstrate that incubation of methylamine in the presence of SSAO-rich tissues, e.g., human brain meninges, results in formaldehyde-protein cross-linkage of particulate bound proteins as well as of soluble proteins. This cross-linkage can be completely blocked by a selective inhibitor of SSAO. Our data support the hypothesis that the SSAO-induced production of formaldehyde may be involved in the alteration of protein structure, which may subsequently cause protein deposition associated with chronic pathological disorders.
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PMID:Protein cross-linkage induced by formaldehyde derived from semicarbazide-sensitive amine oxidase-mediated deamination of methylamine. 1512 65

Previous studies have demonstrated endogenous formaldehyde (FA) may be involved in endothelial damage, and may be a potential factor of vulnerability of atherosclerosis. However, the mechanism has not been characterized. The present studies examined DNA-protein cross-links (DPC) formation in rat aorta endothelial cells (RAECs) treated with formaldehyde, hydrogen peroxide (H2O2), or formaldehyde with equal molar concentration of H2O2, which is produced with formaldehyde in the body at the same time. Using a K+/SDS precipitation assay for DPC determination, concentration-dependent increases in DPC formation were observed 1.5 h after treatment of RAECs with 0.01-2mM FA, H2O2, or FA with equal molar concentration of H2O2. Time-dependent increases in DPC formation were also observed at 0.5-4 h time point after treatment of RAECs with 0.05 and 0.1mM FA, or 0.1mM FA with H2O2. The DPC levels reduced after treatment with FA and equal molar concentration of H2O2, compared with treatment with FA alone. FA may be less cytotoxic, as FA alone did not affect the cell viability even treating for 4h, until the treatment concentration reached 2mM. However, H2O2, and FA with H2O2 induced significant decreases of cell viability. These studies suggest that FA and H2O2 may injure endothelial cells synergistically, and low concentration of FA (0.05-0.1) may contribute to the endothelial injury in the body during aging.
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PMID:The effect of endogenous formaldehyde on the rat aorta endothelial cells. 1596 Dec 63


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