Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we discovered a T(-786)-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene that is associated with coronary spasm. The precise mechanism(s) of myocardial infarction (MI), especially without coronary organic stenosis, has not been elucidated, but it seems possible that coronary spasm plays a key role in the mechanism. In this study, we examined the frequency with which the T(-786)-->C mutation occurred in 359 patients with MI who were compared with 195 controls. In the MI group, the frequency of C/C, C/T, and T/T genotypes was 1%, 22%, and 77%, respectively. In the control group, the frequency of C/C, C/T, and T/T genotypes were 0%, 8%, and 92%, respectively. The frequency of the C allele was significantly higher in the MI group than in the control group (p < 0.001). In the MI group, 30 of 359 patients (8%) with MI had no stenosed vessels angiographically, 158 (44%) had 1 stenosed vessel, 80 (22%) had 2 stenosed vessels, and 91 (25%) exhibited 3 stenosed vessels. Total and low-density lipoprotein cholesterol levels and the incidence of diabetes mellitus increased as the number of stenosed vessels increased (p < 0.01, respectively). The frequency of the T(-786)-->C mutation was significantly higher in MI patients with no stenosed vessels (50%) than in those with stenosed vessels (p < 0.003). In conclusion, the T(-786)-->C mutation was strongly associated with MI, especially without coronary arterial stenosis, in Japanese patients. The association may be due to the impaired effects of nitric oxide in the cardiovascular system.
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PMID:T(-786)--> C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction, especially without coronary organic stenosis. 1098 Feb 13

1. We investigated the effects of chronic pravastatin treatment on the impaired endothelium-dependent relaxation seen in aortae from established streptozotocin (STZ)-induced diabetic rats. Starting at 6 weeks of diabetes, pravastatin (10 mg kg(-1)) was administered to STZ-induced diabetic rats for 4 weeks. 2. The increased total cholesterol and low-density lipoprotein (LDL) cholesterol levels seen in STZ-induced diabetic rats were not restored to normal by pravastatin. Aortae from pravastatin-treated diabetic rats did not show an impaired endothelium-dependent relaxation to acetylcholine. The expression of the mRNA for endothelial nitric oxide synthase was unaffected by diabetes or pravastatin. 3. The enhanced level of malondialdehyde (MDA)-modified LDL seen in STZ-induced diabetic rats was normalized by pravastatin treatment. The resistance of LDL to oxidation was assessed by measuring the amount of MDA or conjugated dienes generated by incubation with copper ions. LDL isolated from diabetic rats, but not those from pravastatin-treated diabetics, showed enhanced the susceptibility to oxidation, but incubation in vitro with pravastatin had no effect on LDL oxidation. 4. Following incubation of control aortae for 6 h with LDL (0.1 mg protein ml(-1)) isolated from diabetic rats, the endothelium-dependent relaxation to acetylcholine or A23187 was impaired, but LDL isolated from control or pravastatin-treated rats had no such effect. This inhibitory effect of diabetic LDL was prevented by superoxide dismutase (SOD), a superoxide scavenger. 5. These results suggest that pravastatin preserves endothelial function in aortae from STZ-induced diabetic rats without lowering plasma cholesterol, and its effect may be due to decreased LDL oxidation.
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PMID:Mechanisms underlying the chronic pravastatin treatment-induced improvement in the impaired endothelium-dependent aortic relaxation seen in streptozotocin-induced diabetic rats. 1099 15

Accumulating evidence suggests that oxidant stress alters many functions of the endothelium, including modulation of vasomotor tone. Inactivation of nitric oxide (NO(.)) by superoxide and other reactive oxygen species (ROS) seems to occur in conditions such as hypertension, hypercholesterolemia, diabetes, and cigarette smoking. Loss of NO(.) associated with these traditional risk factors may in part explain why they predispose to atherosclerosis. Among many enzymatic systems that are capable of producing ROS, xanthine oxidase, NADH/NADPH oxidase, and uncoupled endothelial nitric oxide synthase have been extensively studied in vascular cells. As the role of these various enzyme sources of ROS become clear, it will perhaps be possible to use more specific therapies to prevent their production and ultimately correct endothelial dysfunction.
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PMID:Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. 1107 78

Glucose transport in skeletal muscle is stimulated by two distinct stimuli, insulin and exercise. The mechanism by which exercise stimulates glucose transport is not known, although it is distinct from the insulin-mediated pathway. Recently, it has been shown that AMP-activated protein kinase (AMPK) is activated by exercise in skeletal muscle, whereas pharmacological activation of AMPK by 5-amino-4-imidazolecarboxamide riboside (AICAR) leads to increased glucose transport. It has been postulated, therefore, that AMPK may be the link between exercise and glucose transport. To address this, we have examined the signaling pathway involved in the stimulation of glucose uptake after activation of AMPK. Here we show that activation of AMPK by AICAR in rat muscle and mouse H-2Kb muscle cells activates glucose transport approximately twofold. AMPK in H-2Kb cells is also activated by hyperosmotic stress and the mitochondrial uncoupling agent, dinitrophenol, both of which lead to increased glucose transport. In contrast, insulin, which activates glucose transport two- to-threefold in both rat muscle and H-2Kb cells, has no effect on AMPK activity. A previous study has shown that AMPK phosphorylates and activates endothelial nitric oxide synthase (NOS). We show here that NOS activity in H-2Kb cells is activated after stimulation of AMPK by AICAR. Treatment of H-2Kb cells or rat muscle with NOS inhibitors completely blocks the increase in glucose transport after activation of AMPK. In addition, an inhibitor of guanylate cyclase also blocks activation of glucose transport by AICAR in H-2Kb cells. These results indicate that activation of AMPK in muscle cells stimulates glucose transport by activation of NOS coupled to downstream signaling components, including cyclic GMP.
Diabetes 2000 Dec
PMID:Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. 1111 97

Endothelial dysfunction accompanies suboptimal glucose control in patients with diabetes mellitus. A hallmark of endothelial dysfunction is a deficiency in production or bioavailability of vascular nitric oxide (NO). Here we demonstrate that acute exposure of human endothelial cells to glucose, at levels found in plasma of diabetic patients, results in a significant blunting of NO responses to the endothelial nitric oxide synthase (eNOS) agonists bradykinin and A-23187. Monitoring of NO generation by purified recombinant bovine eNOS in vitro, using amperometric electrochemical detection and an NO-selective porphyrinic microelectrode, showed that glucose causes a progressive and concentration-dependent attenuation of detectable NO. Addition of glucose to pure NO solutions similarly elicited a sharp decrease in NO concentration, indicating that glucose promotes NO loss. Electrospray ionization-tandem mass spectrometry, using negative ion monitoring, directly demonstrated the occurrence of a covalent reaction involving unitary addition of NO (or a derived species) to glucose. Collectively, our findings reveal that hyperglycemia promotes the chemical inactivation of NO; this glucose-mediated NO loss may directly contribute to hypertension and endothelial dysfunction in diabetic patients.
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PMID:Glucose scavenging of nitric oxide. 1118 10

Monitoring of 24-hour ambulatory blood pressure(ABPM), measurements of circulating vasoactive substances and microalbuminuria, and assessment of gene polymorphisms as genetic markers are introduced to detect and evaluate hypertension. Classifications of ABPM based on impact on risks of cardiovascular diseases have been currently available. Plasma level of brain natriuretic peptide(BNP), a cardiac hormone, increases markedly in congestive heart failure, in proportion to its severity, and is evaluated as a potential index of severity of heart failure. In addition, serum level of hepatocyte growth factor(HGF), a member of endothelium specific growth factors, in hypertension might be useful for evaluating the presence of complications and degree of endothelial dysfunction. In diabetes mellitus, onset of microalbuminuria appeared as an important sign of early nephropathy. There is growing evidence that microalbuminuria is an independent predictor of atherosclerosis and premature death in the general population. Current studies have shown that gene polymorphisms including components of the renin-angiotensin-aldosterone system may be possible genetic markers for hypertension and its associated cardiovascular diseases. Our data suggest positive linkages between hypertension and 4 gene polymorphisms including angiotensinogen Met235Thr, angiotensin converting enzyme I/D, aldosterone synthase CYP11B2 T-344C, and endothelial nitric oxide synthase Glu298Asp in the Aomori population.
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PMID:[New techniques and laboratory examinations in the detection and evaluation of hypertension]. 1130 25

Vascular endothelial growth factor (VEGF) is a cytokine that potently stimulates angiogenesis, microvascular hyperpermeability, and endothelium-dependent vasodilation, effects that are largely mediated by endothelial nitric oxide synthase (eNOS). The expression of VEGF is pronounced in glomerular visceral epithelial cells, but its function in renal physiology and pathophysiology is unknown. VEGF expression is upregulated by high ambient glucose concentrations in several cell types in vitro and in glomeruli of diabetic rats. To assess the role of VEGF in the pathophysiology of early renal dysfunction in diabetes, monoclonal anti-VEGF antibodies (Ab) were administered to control and streptozotocin-induced diabetic rats for 6 wk after induction of diabetes. Based on in vitro binding studies, an adequate serum VEGF inhibitory activity was achieved during the entire course of anti-VEGF Ab administration. Anti-VEGF Ab treatment but not administration of isotype-matched control Ab decreased hyperfiltration, albuminuria, and glomerular hypertrophy in diabetic rats. VEGF blockade also prevented the upregulation of eNOS expression in glomerular capillary endothelial cells of diabetic rats. Antagonism of VEGF had no effect on GFR and glomerular volume in control rats. These results identify VEGF as a pathogenetic link between hyperglycemia and early renal dysfunction in diabetes. Targeting VEGF may prove useful as a therapeutic strategy for the treatment of early diabetic nephropathy.
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PMID:Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. 1131 58

The effect of the synthetic statin fluvastatin was investigated on the concentrations of endothelial nitric oxide synthase (eNOS) and of soluble adhesion molecules in human vascular endothelial cell cultures. Fluvastatin was able to increase dose-dependently eNOS concentration. In addition, fluvastatin reduced concentrations of E-Selectin and ICAM-1. These results further support the evidence that statins elicit important effects on the vascular endothelium which may contribute to the reduction of morbidity and mortality of cardiovascular diseases.
Exp Clin Endocrinol Diabetes 2001
PMID:Further evidence for direct vascular actions of statins: effect on endothelial nitric oxide synthase and adhesion molecules. 1140 2

This study examined skeletal muscle microvessel reactivity to constrictor stimuli in obese (OZR) versus lean Zucker rats (LZR). Gracilis arteries from both rat groups were isolated, cannulated with glass micropipettes, and viewed via television microscopy. Changes in vessel diameter were measured with a video micrometer. Arterial constriction to norepinephrine was elevated in OZR versus LZR, although vasoconstrictor reactivity to endothelin and angiotensin II was unaltered. Differences in reactivity between vessels of LZR and OZR were not explained by the loss of either endothelial nitric oxide synthase or beta-adrenergic receptor function. Reactivity of in situ cremasteric arterioles of OZR to norepinephrine was elevated versus LZR. Treatment with prazosin increased the diameter of in vivo gracilis arteries of OZR to levels determined in LZR and also normalized blood pressure in OZR. These results suggest that the constrictor reactivity of skeletal muscle microvessels in OZR is heightened in response to alpha-adrenergic stimuli and that development of diabetes in OZR may be associated with impaired skeletal muscle perfusion and hypertension due to microvessel hyperreactivity in response to sympathetic stimulation.
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PMID:Augmented adrenergic vasoconstriction in hypertensive diabetic obese Zucker rats. 1183 74

Leukocyte adhesion to the diabetic retinal vasculature results in early blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell injury and death. Previous work has shown that intercellular adhesion molecule-1 (ICAM-1) and CD18 are required for these processes. However the relevant in vivo stimuli for ICAM-1 and CD18 expression in diabetes remain unknown. The current study investigated the causal role of endogenous vascular endothelial growth factor (VEGF) and nitric oxide in initiating these events. Diabetes was induced in Long-Evans rats with streptozotocin, resulting in a two- to threefold increase in retinal leukocyte adhesion. Confirmed diabetic animals were treated with a highly specific VEGF-neutralizing Flt-Fc construct (VEGF TrapA(40)). Retinal ICAM-1 mRNA levels in VEGF TrapA(40)-treated diabetic animals were reduced by 83.5% compared to diabetic controls (n = 5, P < 0.0001). VEGF TrapA(40) also potently suppressed diabetic leukocyte adhesion in retinal arterioles (47%, n = 11, P < 0.0001), venules (36%, n = 11, P < 0.0005), and capillaries (36%, n = 11, P < 0.001). The expression of endothelial nitric oxide synthase (eNOS), a downstream mediator of VEGF activity, was increased in diabetic retina, and was potently suppressed with VEGF TrapA(40) treatment (n = 8, P < 0.005). Further, VEGF TrapA(40) reduced the diabetes-related nitric oxide increases in the retinae of diabetic animals. The inhibition of eNOS with N-omega-nitro-L-arginine methyl ester also potently reduced retinal leukocyte adhesion. Although neutrophil CD11a, CD11b, and CD18 levels were increased in 1-week diabetic animals, VEGF TrapA(40) did not alter the expression of these integrin adhesion molecules. Taken together, these data demonstrate that VEGF induces retinal ICAM-1 and eNOS expression and initiates early diabetic retinal leukocyte adhesion in vivo. The inhibition of VEGF bioactivity may prove useful in the treatment of the early diabetic retinopathy.
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PMID:Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. 1183 70


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