Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study evaluated the effects of the selective inducible nitric oxide synthase (iNOS) inhibitor N-[3-(aminomethyl)benzyl]acetamidine (1400W) on the microcirculation in reperfused skeletal muscle. The cremaster muscles from 32 rats underwent 5 h of ischemia followed by 90 min of reperfusion. Rats received either 3 mg/kg 1400W or PBS subcutaneously before reperfusion. We found that blood flow in reperfused muscles was <45% of baseline in controls but sharply recovered to near baseline levels in 1400W-treated animals. There was a significant (P < 0.01 to P < 0.001) difference between the two groups at each time point throughout the 90 min of reperfusion. Vessel diameters remained <80% of baseline in controls during reperfusion, but recovered to the baseline level in the 1400W group by 20 min, and reached a maximum of 121 +/- 14% (mean +/- SD) of baseline in 10- to 20-micro m arterioles, 121 +/- 6% in 21- to 40-micro m arterioles, and 115 +/- 8% in 41- to 70-micro m arteries (P < 0.01 to P < 0.001). The muscle weight ratio between ischemia-reperfused (left) and non-ischemia-reperfused (right) cremaster muscles was 193 +/- 42% of normal in controls and 124 +/- 12% in the 1400W group (P < 0.001). Histology showed that neutrophil extravasation and edema were markedly reduced in 1400W-treated muscles compared with controls. We conclude that ischemia-reperfusion leads to increased generation of NO from iNOS in skeletal muscle and that the selective iNOS inhibitor 1400W reduces the negative effects of ischemia-reperfusion on vessel diameter and muscle blood flow. Thus 1400W may have therapeutic potential in treatment of ischemia-reperfusion injury.
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PMID:Reperfusion injury is reduced in skeletal muscle by inhibition of inducible nitric oxide synthase. 1250 43

The present study was done to determine the effect of trolox C, a hydrophilic analogue of vitamin E, on hepatic injury, especially the alteration in cytochrome P-450 (CYP)-dependent drug metabolism during ischemia and reperfusion (I/R). Rats were subjected to 60 min of hepatic ischemia and 5 h of reperfusion. Rats were treated intravenously with trolox C (2.5 mg/kg) or vehide (PBS, pH 7.4), 5 min before reperfusion. Serum alanine aminotransferase and lipid peroxidation levels were markedly increased after I/R. This increase was significantly suppressed by trolox C. Cytochrome P-450 content was decreased after I/R but was restored by trolox C. There were no significant differences in ethoxyresorufin O-dealkylase (CYP 1A1) and methoxyresorufin O-dealkylase (CYP 1A2) activities among any of the experimental groups. Pentoxyresorufin O-dealkylase (CYP 2B1) activity was decreased and aniline p-hydroxylase (CYP 2E1) activity was increased after I/R. Both these changes were prevented by trolox C. Our findings suggest that trolox C reduces hepatocellular damage as indicated by abnormalities in microsomal drug-metabolizing function during I/R, and that this protection is, in part, caused by decreased lipid peroxidation.
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PMID:Trolox C ameliorates hepatic drug metabolizing dysfunction after ischemia/reperfusion. 1251 Aug 51

Heme oxygenase-1 (HO-1) overexpression using gene transfer protects rat livers against ischemia/reperfusion (I/R) injury. This study evaluates the effects of Ad-HO-1 gene transfer in a rat renal isograft model. Donor LEW kidneys were perfused with Ad-HO-1, Ad-beta-gal, or PBS, stored at 4 degrees C for 24 h, and transplanted orthotopically into LEW recipients, followed by contralateral native nephrectomy. Serum creatinine, urine protein/creatinine ratios, severity of histologic changes, HO-1 mRNA/protein expression, and HO enzymatic activity were analyzed. Ad-HO-1 gene transfer conferred a survival advantage when compared with PBS- and Ad-beta-gal-treated controls, with median survival of 100, 7, and 7 d, respectively (P < 0.01). Serum creatinine levels were elevated at day 7 in all groups (range, 2.2 to 5.8 mg/dl) but recovered to 1.0 mg/dl by day 14 (P < 0.01) in Ad-HO-1 group, which was sustained thereafter. Urine protein/creatinine ratio at day 7 was elevated in both PBS and Ad-beta-gal, as compared with the Ad-HO-1 group (12.0 and 9.8 versus 5.0; P < 0.005); histologically, ATN and glomerulosclerosis was more severe in Ad-beta-gal group at all time points. Reverse transcriptase-PCR-based HO-1 gene expression was significantly increased before reperfusion (P < 0.001) and remained increased in the Ad-HO-1-treated group for 3 d after transplantation. Concomitantly, HO enzymatic activity was increased at transplantation and at 3 d posttransplant in the Ad-HO-1 group, compared with Ad-beta-gal controls (P < 0.05); tubular HO-1 expression was discernible early posttransplant in the Ad-HO-1 group alone. These findings are consistent with protective effects of HO-1 overexpression using a gene transfer approach against severe renal I/R injury, with reduced mortality and attenuation of tissue injury.
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PMID:Gene transfer-induced local heme oxygenase-1 overexpression protects rat kidney transplants from ischemia/reperfusion injury. 1259 12

Delivery of DNA mixed with a degradable matrix carrier was supposed to improve transgene expression. Using a rabbit hind-limb ischemia model, we tested the angiogenic potency of plasmid encoding human vascular endothelial growth factor (pSG5-VEGF165) entrapped in fibrin sealant. Animals were injected intramuscularly with 500 microg of pSG5-VEGF165 or control plasmid, dissolved in saline (PBS) or fibrin glue. After 14 days, presence of delivered constructs and expression of transgene was confirmed in injected muscles of all animals. There were no significant differences in the levels of human VEGF mRNA and protein between VEGF-PBS and VEGF-fibrin groups (Mann-Whitney test). Accordingly, pSG5-VEGF165 regardless of the way of delivery, induced similar increases in capillary density within treated muscles (ANOVA). Control plasmid did not show any effects. In conclusion, injection of pSG5-VEGF165 into ischemic adductor muscle leads to synthesis of human VEGF and increases the number of capillaries. Fibrin carrier does not influence its angiogenic potential.
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PMID:Delivery of high dose VEGF plasmid using fibrin carrier does not influence its angiogenic potency. 1265 51

Amino acid transport across the plasma membrane is essential for supplying enterocytes with amino acids for cellular metabolism. We studied amino acid transport during ischemic conditions using human intestinal epithelial cell line Caco-2. Cells were incubated under nutrient-deprived (phosphate-buffered saline, PBS), hypoxic, and ischemic (PBS+hypoxia) conditions. Ischemia resulted in a significant decrease in glutamine transport by a mechanism that decreased V(max) without affecting K(m). The expression of system ATB degrees (glutamine transporter) mRNA decreased in the ischemic and nutrient-deprived groups, suggesting that the down-regulation of glutamine transport is due to modification of expression of the ATB degrees gene. The transport of glutamate and leucine, DNA synthesis, and intracellular glutathione also decreased in the ischemic group. These findings throw some light on the mechanism of intestinal epithelial damage during ischemia.
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PMID:Amino acid transport is down-regulated in ischemic human intestinal epithelial cells. 1472 41

Mechanisms that hinder ischemia-induced neovascularization in diabetes remain poorly understood. We hypothesized that endogenous bone marrow mononuclear cell (BM-MNC) dysfunction may contribute to the abrogated postischemic revascularization reaction associated with diabetes. We first analyzed the effect of diabetes (streptozotocin, 40 mg/kg) on BM-MNC pro-angiogenic potential in a model of surgically induced hindlimb ischemia. In nondiabetic animals, transplantation of BM-MNCs isolated from nondiabetic animals raised the ischemic/nonischemic angiographic score, capillary number, and blood flow recovery by 1.8-, 2.7-, and 2.2-fold, respectively, over that of PBS-injected nondiabetic animals (P < 0.05). Administration of diabetic BM-MNCs also improved the neovascularization reaction in ischemic hindlimbs of nondiabetic mice but to a lesser extent from that observed with nondiabetic BM-MNC transplantation. In diabetic mice, injection of nondiabetic BM-MNCs was still more efficient than that of diabetic BM-MNCs. Such BM-MNC dysfunction was associated with the impairment of diabetic BM-MNC capacity to differentiate into endothelial progenitor cells (EPCs) in vitro and to participate in vascular-like structure formation in a subcutaneous Matrigel plug. Placenta growth factor (PlGF) administration improved by sixfold the number of EPCs differentiated from diabetic BM-MNCs in vitro and enhanced ischemic/nonischemic angiographic score, capillary number and blood flow recovery by 1.9-, 1.5- and 1.6-fold, respectively, over that of untreated diabetic animals (P < 0.01). Endogenous BM-MNC pro-angiogenic potential was affected in diabetes. Therapeutic strategy based on PlGF administration restored such defects and improved postischemic neovascularization in diabetic mice.
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PMID:Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. 1474 52

We have previously shown that atherosclerotic apolipoprotein E-deficient (apoE(-/-)) x LDL receptor-deficient (LDLR(-/-)) mice develop myocardial infarction when exposed to hypoxic stress. This study was performed to assess the role of thrombin and thrombosis in this process. ApoE(-/-) x LDLR(-/-) mice were fed a cholesterol-rich diet for 8 mo and were then subjected to hypoxic stress while receiving isoflurane anesthesia. One group received a bolus dose (5.6 micromol/kg) of the thrombin inhibitor melagatran, and control animals received PBS 10 min before the hypoxic stress. The mice were exposed to 10 min of hypoxia followed by normoxia. Ten minutes after the stress, Alzet pumps delivering melagatran (20 nmol x kg x (-1)min(-1)) or PBS were implanted, and the mice were allowed to recover for 48 h. The cardiac response was analyzed by histology, immunohistochemistry, and serum troponin T assay. All animals showed reversible ECG changes as a sign of ischemia during hypoxic stress, and 50% developed infarctions afterward as judged by troponin T levels. The group that received thrombin inhibitor had significantly lower troponin T and smaller myocardial infarctions than the PBS-treated group. These data show that thrombin generation is an important pathogenetic factor and suggest that coronary thrombosis is involved in myocardial infarction in atherosclerotic mice. Exposure of atherosclerotic mice to hypoxia leads to myocardial infarction through a two-phase pathway in which acute transient ischemia is followed by thrombin-dependent, irreversible, myocardial ischemia and myocardial cell death.
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PMID:Thrombin inhibitor reduces myocardial infarction in apoE-/- x LDLR-/- mice. 1503 Nov 24

Therapeutic angiogenesis is the growth of blood vessels from a pre-existing vasculature for clinical applications such as treating myocardial and limb ischemia. Vascular endothelial growth factor (VEGF) is a potent signal transduction molecule that acts specifically on vascular endothelial cells. Encapsulation of VEGF in a polymer matrix not only protects protein against enzymatic degradation in the body, but also allows proteins to be released at a controllable rate into a localized area. In this study, VEGF was encapsulated in calcium alginate beads by the extrusion/external gelation method, and was subsequently released in PBS and in serum media. The objective was to optimize VEGF encapsulation yield and obtain VEGF release at a constant rate from alginate matrices in vitro. The incorporation of low concentrations of VEGF and NaCl can increase encapsulation yield to 97%. The rate of VEGF release from alginate beads was higher in serum than in PBS, which was due to the capacity of the serum in reducing the electrostatic interaction between alginate and VEGF. The presence of CaCl(2) in the release supernatant can shield the alginate interaction with VEGF, and a constant release rate of 6 ng/ml/day may be sustained for 14 days. These results suggest that the alginate-VEGF delivery system may be useful in the development of vascular tissue engineering and wound healing applications.
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PMID:Sustained delivery of vascular endothelial growth factor with alginate beads. 1512 Sep 2

Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography, is weak. In this study, we report an angiogenesis-independent effect of VEGF on ischemic skeletal muscle, ie, upregulation of myoglobin after VEGF treatment. Mice received intramuscular injection with adenoviral VEGF-A or either adenoviral LacZ or PBS as control, followed by surgical induction of acute hindlimb ischemia at day 3. At day 6, capillary density was increased in calf muscle of Ad.VEGF-treated versus control mice (P<0.01). However, angiographic score of collateral arteries was unchanged between Ad.VEGF-treated and control mice. More interestingly, an increase in myoglobin was observed in Ad.VEGF-treated mice. Active myoglobin was 1.5-fold increased in calf muscle of Ad.VEGF-treated mice (P< or =0.01). In addition, the number of myoglobin-stained myofibers was 2.6-fold increased in Ad.VEGF-treated mice (P=0.001). Furthermore, in ischemic muscle of 15 limb amputation patients, VEGF and myoglobin were coexpressed. Finally, in cultured C2C12 myotubes treated with rhVEGF, myoglobin mRNA was 2.8-fold raised as compared with PBS-treated cells (P=0.02). This effect could be blocked with the VEGF receptor tyrosine kinase inhibitor SU5416. In conclusion, we show that VEGF upregulates myoglobin in ischemic muscle both in vitro and in vivo. Increased myoglobin expression in VEGF-treated muscle implies an improved muscle oxygenation, which may, at least partly, explain observed clinical improvements in VEGF-treated patients, in the absence of improved vascularization.
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PMID:Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo. 1524 80

For understanding the relationship between the increased incidence of sudden cardiac death and air pollution, we examined the effects of intratracheal instillation of diesel exhaust particles (DEP) on acute myocardial ischemia/reperfusion-induced arrhythmia in rats. The animals received 1 mg DEP 24-48 h before the ischemia/reperfusion (DEP-pretreated group, DEP-PRE), and were subjected to 3 successive brief ischemia/reperfusion (3 min ischemia followed by 5 min reperfusion) procedures. These were to make the animals tolerant to ischemia/reperfusion-related myocardial deterioration. Thereafter the animals were subjected to a 10-min ischemia followed by a 30-min reperfusion. In the experiments, an increased mortality was observed in the DEP-PRE group compared to the vehicle (0.05% Tween 80-PBS)-treated group. Forty-six percent of the animals in DEP-PRE died during the first 3-min reperfusion period. The animals of other groups were intratracheally instilled with DEP at the beginning of ischemia/reperfusion experiment, or were pretreated with polyethylene glycol-conjugated superoxide dismutase (1000 IU kg(-1), iv). In these animals, incidences of both arrhythmia and mortality were similar to those in the animals treated with the vehicle. In experiments to investigate the effects of DEP on the biochemical and hematological parameters, neutrophil count was elevated by a higher dose (5 mg) of DEP at 24 h after the intratracheal instillation, and oxygen radical production, which was induced by 12-O-tetradecanoylphorbol 13-acetate, was enhanced at 72 h. These results indicate that intratracheal DEP instillation exacerbates short-period ischemia/reperfusion-induced arrhythmia. Delivery and activation of peripheral neutrophils and oxygen radicals produced in neutrophils might participate in this exacerbation. This is the first article that demonstrates the arrhythmogenicity of DEP using intratracheal instillation in rats.
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PMID:Delayed exacerbation of acute myocardial ischemia/reperfusion-induced arrhythmia by tracheal instillation of diesel exhaust particles. 1537 Nov 83


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