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)

Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the etiology of atherosclerosis. Oxidized LDL that accumulates in atherosclerotic plaques is known to exhibit a characteristic fluorescence with excitation and emission near 360 and 430 nm, respectively. (E)-4-Hydroxy-2-nonenal (HNE), formed during LDL oxidation, is capable of modifying LDL to generate the same fluorescent signature. The HNE-derived fluorophore was shown by us to possess a 2-hydroxy-2-pentyl-1,2-dihydropyrrol-3-one iminium (HPDPI) structure. We herein report the synthesis of the HPDPI-derived lysine-lysine cross-link needed as a standard reference for HPLC quantitation of the cross-link in protein hydrolysates. The main focus of the current work, however, is the design and development of two polyclonal antibodies against the HPDPI epitope. Utilizing these antibodies, levels of the HPDPI epitope were estimated in HNE-treated bovine serum albumin and in copper-oxidized LDL by an enzyme-linked immunosorbent assay. Our results are consistent with the premise that the fluorescent HPDPI cross-link is a key contributor to the fluorescence exhibited by atherosclerotic lesions.
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PMID:Polyclonal antibodies to a fluorescent 4-hydroxy-2-nonenal (HNE)-derived lysine-lysine cross-link: characterization and application to HNE-treated protein and in vitro oxidized low-density lipoprotein. 1081 58

Covalent conjugation of a photosensitizer to a ligand that specifically recognized and internalized by a cell-surface receptor may be a way of improving the selectivity of photodynamic therapy (PDT). The class A Type-I scavenger receptor of macrophages, which among other ligands recognizes maleylated serum albumin and has a high capacity is a good candidate for testing this approach. Chlorin(e6) was covalently attached to bovine serum albumin to give conjugates with molar substitution ratios of 1:1 and 3:1 (dye to protein), and these conjugates could then be further modified by maleylation. A novel way of purifying the conjugates by acetone precipitation was developed in order to remove traces of unbound dye that could not be accomplished by size-exclusion chromatography. Conjugates were characterized by polyacrylamide gel electrophoresis and thin-layer chromatography. Photosensitizer uptake was measured by target J774 murine macrophage-like cells and nontarget OVCAR-5 human ovarian cancer cells, and phototoxicity was examined after illumination by a 660 nm diode laser by a tetrazolium assay. All of the purified conjugates were taken up by and after illumination killed J774 cells while there was only small uptake and no phototoxicity toward OVCAR-5 cells. The higher dye:protein ratio and maleylation of the conjugates both produced higher uptakes and lower survival ratios in J774 cells. The uptake and phototoxicity by J774 cells were decreased after incubation at 4 degrees C demonstrating internalization, and confocal microscopy with organelle-specific green fluorescent probes showed largely lysosomal localization. Uptake and phototoxicity by J774 cells could both be competed by addition of the scavenger receptor ligand maleylated albumin. These data show that scavenger receptor-targeted PDT gives a high degree of specificity toward macrophages and may have applications in the treatment of tumors and atherosclerosis.
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PMID:Scavenger-receptor targeted photodynamic therapy. 1104 26

Two methods for the analysis of antioxidants, based on polyacrylamide gel electrophoresis (PAGE) and gel permeation high performance liquid chromatography (HPLC) were developed. Both of them exploit the variations of the signal (band or peak) given by human serum albumin (0.2% w/v in 100 mM sodium phosphate pH 7) upon oxidation with hypochlorite (1% of a solution containing 4% active Cl), quantitatively determined by densitometric analysis or peak integration. Based on such changes, two formulas were defined which allowed the determination of the antioxidant activity of ascorbic acid (EC(50,PAGE)=4.8x10(-4) M, EC(50,HPLC)=3.6x10(-4) M), glutathione (EC(50,PAGE)=1.5x10(-4) M, EC(50,HPLC)=2.0x10(-4) M) and melatonin (EC(50,PAGE)=5.2x10(-4) M, EC(50,HPLC)=3.2x10(-4) M), chosen as reference compounds. A good correlation was found between the activities of these substances in the two assays, which are also in good agreement with literature data, indicating that the two methods are essentially equivalent. These assays could be useful for the screening of new antioxidant drugs for pathological conditions such as cataract, rheumatic diseases, atherosclerosis and Alzheimer's disease.
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PMID:In vitro evaluation of antioxidant activity by electrophoresis and high performance liquid chromatography. 1111 64

Hypothyroid (thyroid stimulating hormone (TSH)> or =20 mIU/l; N=32) participants in the third National Health and Nutrition Examination Survey, Phase 2 (1991-1994) were compared with non-hypothyroid subjects (0.5 mIU/l<TSH<20 mIU/l; N=6490) to examine the relationship between hypothyroidism and hyperhomocysteinemia (serum total homocysteine>12 micromol/l) and hypercholesterolemia (serum total cholesterol>6.2 mmol/l). After controlling for age, gender, and race ethnicity, the odds ratios (95% confidence interval (CI)) relating hypothyroidism to hyperhomocysteinemia and high total cholesterol were 4.9 (1.8-14.0) and 8.0 (2.9-21.9), respectively. Based on 26 hypothyroid and 5811 non-hypothyroid subjects with triglyceride concentration < or =2.82 mmol/l, the odds ratio for the relationship between hypothyroidism and high low-density lipoprotein (LDL)-cholesterol (>4.6 mmol/l by the Friedewald equation) was 5.3 (95% CI, 1.3-20.9). Adding additional terms to the multivariate logistic regression model had little effect on the odds ratios relating hypothyroidism to high total or LDL-cholesterol, but adding terms for serum creatinine concentration >123.8 micromol/l and for red blood cell folate and serum vitamin B-12 concentrations resulted in an attenuated, but still significant (P<0.05), odds ratio relating hypothyroidism to hyperhomocysteinemia (2.5; 95% CI, 1.0-6.1). Controlling for cigarette smoking, heart attack/stroke history, body mass index, and serum albumin concentration did not affect the odds ratios. Hyperhomocysteinemia and hypercholesterolemia could help to explain the increased risk for arteriosclerotic coronary artery disease in hypothyroidism.
Atherosclerosis 2001 Mar
PMID:Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Survey. 1122 42

Proliferation of vascular smooth muscle cells (VSMC) contributes to the pathogenesis of atherosclerosis, and glycated serum albumin (GSA, Amadori adduct of albumin) might be a mitogen for VSMC proliferation, which may further be associated with diabetic vascular complications. In this study, we investigated the involvement of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and protein kinase C (PKC), in GSA-stimulated mitogenesis, as well as the functional relationship between these factors. VSMC stimulation with GSA resulted in a marked activation of ERK. The MAPK kinase (MEK) inhibitor, PD98059, blocked GSA-stimulated MAPK activation and resulted in an inhibition of GSA-stimulated VSMC proliferation. GSA also increased PKC activity in VSMC in a dose-dependent manner. The inhibition of PKC by the PKC inhibitors, GF109203X and Rottlerin (PKCdelta specific inhibitor), as well as PKC downregulation by phorbol 12-myristate 13-acetate (PMA), inhibited GSA-induced cell proliferation and blocked ERK activation. This indicates that phorbol ester-sensitive PKC isoforms including PKCdelta are involved in MAPK activation. Thus, we show that the MAPK cascade is required for GSA-induced proliferation, and that phorbol ester-sensitive PKC isoforms contribute to cell activation and proliferation in GSA-stimulated VSMC.
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PMID:Glycated serum albumin-induced vascular smooth muscle cell proliferation through activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by protein kinase C. 1123 43

Atherosclerosis is a major complication of type 2 diabetes. The pathogenesis of this complication is poorly understood, but it clearly involves production in the vascular wall of macrophage (Mo) lipoprotein lipase (LPL). Mo LPL is increased in human diabetes. Peripheral factors dysregulated in diabetes, including glucose and free fatty acids (FAs), may contribute to this alteration. We previously reported that high glucose stimulates LPL production in both J774 murine and human Mo. In the present study, we evaluated the direct effect of FAs on murine Mo LPL expression and examined the involvement of peroxisome proliferator-activated receptors (PPARs) in this effect. J774 Mo were cultured for 24 h with 0.2 mmol/l unsaturated FAs (arachidonic [AA], eicosapentaenoic [EPA], and linoleic acids [LA]) and monounsaturated (oleic acid [OA]) and saturated FAs (palmitic acid [PA] and stearic acid [SA]) bound to 2% bovine serum albumin. At the end of this incubation period, Mo LPL mRNA expression, immunoreactive mass, activity, and synthetic rate were measured. Incubation of J774 cells with LA, PA, and SA significantly increased Mo LPL mRNA expression. In contrast, exposure of these cells to AA and EPA dramatically decreased this parameter. All FAs, with the exception of EPA and OA, increased extra- and intracellular LPL immunoreactive mass and activity. Intracellular LPL mass and activity paralleled extracellular LPL mass and activity in all FA-treated cells. In Mo exposed to AA, LA, and PA, an increase in Mo LPL synthetic rate was observed. To evaluate the role of PPARs in the modulatory effect of FAs on Mo LPL gene expression, DNA binding assays were performed. Results of these experiments demonstrate an enhanced binding of nuclear proteins extracted from all FA-treated Mo to the peroxisome proliferator-response element (PPRE) consensus sequence of the LPL promoter. PA-, SA-, and OA-stimulated binding activity was effectively diminished by immunoprecipitation of the nuclear proteins with anti-PPAR-alpha antibodies. In contrast, anti-PPAR-gamma antibodies only significantly decreased AA-induced binding activity. Overall, these results provide the first evidence for a direct regulatory effect of FAs on Mo LPL and suggest a potential role of PPARs in the regulation of Mo LPL gene expression by FAs.
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PMID:Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs. 1124 88

Decreased serum bilirubin levels have been associated with coronary heart disease (CHD). It is believed that bilirubin acts as an antioxidant, preventing formation of oxidized LDL and subsequent atherosclerosis. Serum bilirubin also segregates as a major gene, with the rarer genotype associated with elevated bilirubin levels and occurring in about 12% of the population. Using a large population-based study of random and CHD high risk families, this analysis was designed to replicate the association of lower serum bilirubin levels with early CHD (onset by age 55 for males and 65 for females) using 328 case/control samples and the major gene segregation of bilirubin levels in 555 families. There were significant differences in plasma bilirubin levels between 188 males (12.5 micromol/l) and 140 females (9.3 micromol/l, P<0.0001). Higher serum albumin and lower HDL-C significantly correlated with higher plasma bilirubin levels in females but not males. In sex-specific logistic regression models of early CHD (148 cases and 180 controls), lower plasma bilirubin was associated with increased prevalence of CHD in males with borderline significance (odds ratio=0.93 for a 1 micromol/l increase in bilirubin, P=0.056) but not in females. Bilirubin was found to segregate as a major gene using all 555 families consisting of 1292 individuals, with estimates replicating those in the previously published study. The most parsimonious model was a recessive model for high bilirubin levels that occurred in about 23% of the population. The means were separated by 1.7 standard deviations and there was a significant polygenic effect (h2=0.33, P=0.0009). We conclude that decreased bilirubin is mildly related to CHD in males but not in females. Because of an inverse correlation between HDL-C and bilirubin, the protective high HDL-C levels may have counteracted the CHD risk associated with lower bilirubin levels in females. The inferred major gene for bilirubin may protect against CHD, since elevated levels, rather than lower levels, were associated with this inferred gene.
Atherosclerosis 2001 Feb 15
PMID:Association of plasma bilirubin with coronary heart disease and segregation of bilirubin as a major gene trait: the NHLBI family heart study. 1125 78

In this study the synergistic role of the two haemodynamic parameters, pressure and wall shear stress, in macromolecular transport has been examined across the wall of the rabbit thoracic aorta. Arteries were subjected to 70 and 150 cm water pressure in the presence of fluid flow imposed shear stress. The flux of FITC labelled bovine serum albumin was found to be 3.36+/-1.34 x 10(-6) and 1.99+/-0.77 x 10(-6) cm/s (mean+/-S.D.) after 90 min incubation at 70 and 150 cm water, respectively. The mean relative tissue concentrations were 0.0039+/-0.0025 and 0.012+/-0.007 at 70 and 150 cm water, respectively. Under low values of steady wall shear stress, efflux of BSA is retarded at 150 cm since its tissue concentration is found to be higher than at 70 cm. The net outcome arises as a result of the interaction of increased permeability of endothelial cells exposed to shear stress, the pressure induced distension of the wall matrix and the differential effect of EDRF/NO at the two pressures on medial hydraulic conductivity. In the presence of the EDRF/NO inhibitor L-NAME, reduction in flux of albumin was observed at both the pressures, the decrease being greater at 150 cm water. In the absence of EDRF, the NO synthase independent vasodilator EDHF may be released, which maintains the tone of the medial smooth muscle low. Action of EDHF may be more marked at 150 cm water because NO synthesis is attenuated by higher transmural pressure and the presence of L-NAME eliminates shear stress stimulated NO release. Consequently the dilated vessel will have decreased porosity and less albumin space. The BSA flux across the aorta is, therefore, influenced by both endothelial permeability and permeability of the medial matrix, which are in turn modulated by an interplay of transmural pressure and fluid flow generated shear stress.
Atherosclerosis 2001 Jun
PMID:Interaction of transmural pressure and shear stress in the transport of albumin across the rabbit aortic wall. 1139 28

To test the hypothesis that the cardioprotective effect of alcohol is related to the inhibition of malondialdehyde (MDA) modification of proteins by acetaldehyde (AA), we studied the effect of AA on MDA modification of bovine serum albumin (BSA) in vitro. BSA was incubated simultaneously with a fixed concentration of MDA (70 mM) and different concentrations of AA (120, 60, 30, 10, or 0 mM) for 24 h at 37 degrees C. The MDA-modified or AA-modified BSA was quantitated with immunoblotting by using specific anti-MDA and specific anti-AA protein antisera, respectively. In another set of experiments, BSA was incubated sequentially, first with different concentrations of AA and then with 70 mM of MDA. In both incubation protocols, the presence of AA and AA modification of BSA enhanced MDA binding. These in vitro observations suggest that the putative cardioprotective effects of alcohol or wine cannot be ascribed to AA-mediated reduction in MDA protein formation, a possible biochemical pathway of accelerated atherosclerosis.
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PMID:Malondialdehyde modification of proteins in vitro is enhanced in the presence of acetaldehyde. 1144 83

The aim of this study was to evaluate the effects of advanced glycation end-products (AGEs) on the proliferative activity and fibronectin production of smooth muscle cells (SMCs). AGE-bovine serum albumin (AGE-BSA) was prepared by incubation with D-glucose at 37 degrees C for 60 days. Cultured SMCs were obtained from explants isolated from porcine abdominal aorta and used between passages 3 and 10. The proliferative activity of SMCs was examined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and by incorporation of 3H-thymidine into DNA. Fibronectin production was assessed by competitive ELISA assay for both fibronectin secreted into the culture medium (M-FN) and cell-associated fibronectin (C-FN), i.e., both intra- and peri-cellular fibronectin. Theassay revealed that AGE-BSA did not produce any change in optical density (A570) of SMCs at concentrations of up to 20 microg/ml, but decreased that of SMCs at a concentration of 40 microg/ml. The addition of PDGF (5 ng/ml) induced an increase in 3H-thymidine incorporation into DNA of quiescent SMCs, while the addition of AGE-BSA (20 microg/ml) had no effect. In contrast, AGE-BSA significantly increased C-FN of SMCs (30.8+/-8.58 ng/microg TP), compared to unmodified BSA (16.5+/-4.19 ng/microg TP). However, no difference in M-FN levels was observed between cells treated with AGE-BSA and unmodified BSA. The addition of anti-transforming growth factor (TGF)-beta antibody restored the levels of C-FN in SMCs cultured in 20 microg/ml of AGE-BSA, suggesting that TGF-beta might act as an intermediate factor in AGE-induced fibronectin production by SMCs. Our results suggest that interaction of AGE-modified proteins with SMCs may play a role in the development of atherosclerosis in diabetic and non-diabetic patients.
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PMID:Effects of advanced glycation end products on the proliferation and fibronectin production of smooth muscle cells. 1148 Apr 59


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