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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Islet transplantation represents a potential cure for type 1 diabetes, yet persistent autoimmune and allogeneic immunities currently limit its clinical efficacy. For alleviating the autoimmune destruction of transplanted islets, newly diagnosed NOD mice were provided a single intramuscular injection of recombinant adeno-associated viral vector encoding murine IL-10 (rAAV-IL-10) 4 weeks before renal capsule delivery of 650 syngeneic islets. A dose-dependent protection of islet grafts was observed. Sixty percent (3 of 5) of NOD mice that received a transduction of a high-dose (4 x 10(9) infectious units) rAAV-IL-10 remained normoglycemic for at least 117 days, whereas diabetes recurred within 17 days in mice that received a low-dose rAAV-IL-10 (4 x 10(8) infectious units; 5 of 5) as well as in all of the control mice (5 of 5 untreated and 4 of 4 rAAV-green fluorescent protein-transduced). Serum IL-10 levels positively correlated with prolonged graft survival and were negatively associated with the intensity of autoimmunity. The mechanism of rAAV-IL-10 protection involved a reduction of lymphocytic infiltration as well as induction of antioxidant enzymes manganese superoxide dismutase and heme oxygenase 1 in islet grafts. These studies support the utility of immunoregulatory cytokine gene therapy delivered by rAAV for preventing autoimmune disease recurrence in transplant-based therapies for type 1 diabetes.
Diabetes 2003 Mar
PMID:Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice. 1260 12

To examine whether genes associated with cellular defense against oxidative stress are associated with insulin sensitivity, patients with type 2 diabetes (n = 7) and age-matched (n = 5) and young (n = 9) control subjects underwent a euglycemic-hyperinsulinemic clamp for 120 min. Muscle samples were obtained before and after the clamp and analyzed for heat shock protein (HSP)72 and heme oxygenase (HO)-1 mRNA, intramuscular triglyceride content, and the maximal activities of beta-hydroxyacyl-CoA dehydrogenase (beta-HAD) and citrate synthase (CS). Basal expression of both HSP72 and HO-1 mRNA were lower (P < 0.05) by 33 and 55%, respectively, when comparing diabetic patients with age-matched and young control subjects, with no differences between the latter groups. Both basal HSP72 (r = 0.75, P < 0.001) and HO-1 (r = 0.50, P < 0.05) mRNA expression correlated with the glucose infusion rate during the clamp. Significant correlations were also observed between HSP72 mRNA and both beta-HAD (r = 0.61, P < 0.01) and CS (r = 0.65, P < 0.01). HSP72 mRNA was induced (P < 0.05) by the clamp in all groups. Although HO-1 mRNA was unaffected by the clamp in both the young and age-matched control subjects, it was increased (P < 0.05) approximately 70-fold in the diabetic patients after the clamp. These data demonstrate that genes involved in providing cellular protection against oxidative stress are defective in patients with type 2 diabetes and correlate with insulin-stimulated glucose disposal and markers of muscle oxidative capacity. The data provide new evidence that the pathogenesis of type 2 diabetes involves perturbations to the antioxidant defense mechanism within skeletal muscle.
Diabetes 2003 Sep
PMID:Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism. 1294 74

Gene therapy is the use of gene delivery as a means to achieve high levels of the therapeutic gene product (ie, "drug" delivery) to treat acquired cardiovascular diseases. Human gene therapy for cardiovascular disease is expected to provide important advances in therapeutic angiogenesis, myocardial protection, myocardial regeneration and repair, restenosis, prevention of bypass graft failure, and risk-factor management. The data from ongoing phase 2 and future phase 3 studies will provide evidence to show whether therapeutic angiogenesis is effective, and these studies will identify the types of patients who may benefit. An important therapeutic target is the cell cycle. Data from the Project in Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) I and II studies suggest that a synthetic DNA decoy can sequester the E2F family of transcription factors and arrest cells at the gap period (G1) checkpoint. This mechanism prevents intimal hyperplasia, which is associated with atherosclerosis and coronary graft failure. Administration of a myocardial protective gene (eg, heme oxygenase) via a recombinant adeno-associated virus vector reduces infarct size in animal models of ischemia and reperfusion. Other studies have shown that fractionated bone marrow stem cells promote myocardial repair and regeneration in myocardial infarction. If applied in humans, it will be possible to use a single administration of gene therapy to provide long-term prophylaxis against secondary coronary events and to promote myocardial repair in patients who have experienced an infarct, as well as in those at high risk of myocardial injury. In the future, new technology using stable gene integration may lead to the development of more effective and lifelong therapy for diabetes, familial homozygous hypercholesterolemia, and other acquired diseases.
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PMID:Predicting the future of human gene therapy for cardiovascular diseases: what will the management of coronary artery disease be like in 2005 and 2010? 1461 24

Diabetic cardiomyopathy is responsible for substantial morbidity and mortality in the diabetic population. Increased oxidative stress has been associated with the pathogenesis of chronic diabetic complications including cardiomyopathy. Multiple biochemical mechanisms have been proposed to increase oxidative stress in diabetes. The present study was aimed at elucidating the role of a potent oxidative and cellular stress-responsive system, the heme oxygenase (HO) system, in the heart in diabetes. Streptozotocin-induced diabetic rats were treated with a potent inhibitor of HO system, tin protoporphyrin IX (SnPPIX, 50 micromol/kg/d), and were compared with untreated diabetic and non-diabetic animals. All treatments began at the onset of diabetes, 48 h after injection of streptozotocin along with the confirmation of hyperglycemia. Animals were euthanized after 1 week and 1 month of treatment, and heart tissues were harvested. Frozen tissues were subjected to HO-1 and HO-2 mRNA expression by real-time RT-PCR and HO activity determination. Paraffin-embedded tissue sections were used for immunohistochemical analysis of HO-1 and HO-2. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) stain, a sensitive and specific marker of DNA damage, was preformed to assess damage induced by oxidative stress. In addition, tissue sections were subjected to histochemical analysis for iron. We further examined non-diabetic animals treated with a direct HO agonist, hemin (50 mg/kg/d). A possible relationship between the HO and the nitric oxide (NO) pathways was also considered by studying the mRNA levels of endothelial nitric oxide synthase (NOS) and inducible NOS, and by measuring the amount of NOS products. Our results demonstrate no significant alterations of the HO system following 1 week of diabetes. However, 1 month of diabetes caused increased oxidative stress as demonstrated by higher levels of 8-OHdG-positive cardiomyocytes (80% positive as compared to 11.25% in controls), in association with increased HO isozyme mRNA (2.7-fold increase as compared to controls) and protein expression, and augmented HO activity (759.3 as compared to 312.3 pmol BR/h/mg protein in controls). Diabetic rats further demonstrated increased number of cardiomyocytes with stainable iron. SnPPIX treatment resulted in reduced number of 8-OHdG-positive cardiomyocytes (19.5% as compared to 80% in diabetics) in parallel with reduced HO activity (569.7 as compared to 759.3 pmol BR/h/mg protein in diabetics). Non-diabetic rats treated with HO-agonist hemin exhibited abnormalities similar to diabetic rats. Our results provide the first direct demonstration that diabetes-induced oxidative stress in the heart is, in part, due to upregulated HO expression and activity. These results provide evidence of pro-oxidant activity of HO in the heart in diabetes, which could be mediated by increased redox-active iron.
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PMID:Heme oxygenase in diabetes-induced oxidative stress in the heart. 1465 70

Erectile dysfunction (ED) with aging and diabetes mellitus is caused by impairment of the relaxation evoked by nitric oxide (NO) of penile cavernous smooth muscles and arterioles. However, the mechanism of ED in hypertension is unknown. Carbon monoxide (CO), which is produced by heme oxygenase (HO)-2 in the neuronal system is a neurotransmitter and a vasodilator. We examined the neurogenic role of CO in penile erection and the neurogenic mechanisms of ED in hypertension, using spontaneously hypertensive rats (SHR) or Wistar-Kyoto rats (WKY). The isometric tension of corpus cavernosum tissues from both strains was recorded after guanethidine and atropine treatment. Relaxation in response to electrical field stimulation (EFS) in WKY was suppressed dose-dependently by HO inhibitors both in the absence and presence of an NO synthase (NOS) inhibitor. Reverse transcription-polymerase chain reaction (RT-PCR) showed that the HO-2 gene was expressed in the corpus cavernosum. CO-saturated solution induced a concentration-dependent relaxation in WKY. The neurogenic relaxation to EFS in SHR was impaired as compared with that in WKY after the age of 5 weeks, when blood pressure began to be elevated, due to the attenuated relaxation in response to neurogenic NO and CO. In the corpus cavernosum of SHR, expression of the HO-2 and nNOS genes was similar, and NOx levels after EFS were similar to those of WKY. cGMP levels after EFS and the relaxation evoked by the NO donor was lower in SHR than WKY. Thiobarbituric acid-reacting substance (TBARS) levels were increased, and superoxide dismutase (SOD) activity was suppressed in SHR, as compared with those in WKY, suggesting that the increasing oxidative stress partially causes the impairment of NO-dependent relaxation. These findings suggest that CO regulates the relaxation evoked by EFS in the rat corpus cavernosum, and that ED in hypertension in rats results from an impairment of the relaxation induced by neurogenic CO and NO.
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PMID:Erectile dysfunction in hypertensive rats results from impairment of the relaxation evoked by neurogenic carbon monoxide and nitric oxide. 1512 83

Advanced glycation end products (AGEs) are closely linked to the development of diabetic atherosclerosis. The current study examines the induction of inducible nitric oxide (NO) synthase (iNOS) and heme oxygenase (HO)-1 expression by AGEs, as well as the signaling pathways involved and the interplay between these two enzymes. The stimulation of RAW 264.7 cells with 6.64 or 33.2 microg/ml AGEs leads to HO-1 protein expression, iNOS protein expression, and nitrite accumulation. AGEs lead to the phosphorylation of p42/44 and p38 mitogen-activated protein kinase (MAPK). The inhibition of p42/44 MAPK and protein kinase C prevented, whereas inhibition of p38 MAPK augmented, AGE-induced nitrite release and iNOS expression. In contrast, HO-1 expression was downregulated by inhibition of p38 MAPK. Furthermore, the expression of both proteins was prevented by coincubation with acetovanillone (NADPH oxidase inhibitor). AGE-induced iNOS expression was negatively regulated by stimulation of HO-1 expression with cadmium chloride or endogenous NO. Tin-protoporphyrin IX (HO-1 inhibitor) partially reversed the cadmium chloride-mediated downregulation of iNOS expression. The current study demonstrates that multiple signaling molecules are involved in AGE-stimulated iNOS and HO-1 expression. There also exists a downregulation of iNOS by its own product as well as the products of HO-1.
Diabetes 2004 Jul
PMID:Regulation of inducible nitric oxide synthase expression in advanced glycation end product-stimulated raw 264.7 cells: the role of heme oxygenase-1 and endogenous nitric oxide. 1522 Feb 9

Increased production of reactive oxygen species contributes to the etiology of diabetes complications. Pathophysiological stimuli that increase oxidative stress upregulate heme oxygenase (HO)-1, a cytoprotective heme-degrading enzyme. We hypothesized that HO-1 may be important in myocardial injury that is exacerbated by diabetes. To test this hypothesis, the left anterior descending coronary arteries of nondiabetic and diabetic wild-type (HO-1(+/+)) and HO-1 null (HO-1(-/-)) mice were ligated for 1 h followed by 24 h reperfusion. The absence of HO-1 significantly increased myocardial infarct size (36.4 +/- 2.0 vs. 21.4 +/- 1.8% in HO-1(+/+) mice), while cardiac-specific overexpression of HO-1 protected against myocardial ischemic injury in diabetic mice. Despite similar high blood glucose levels, diabetic HO-1(-/-) mice had fourfold higher oxidative stress and larger infarcts (56.0 +/- 2.8%) than diabetic HO-1(+/+) mice (30.8 +/- 6.1%). Moreover, hyperglycemia increased the mortality of HO-1(-/-) mice (31.3%) after ischemia/reperfusion injury, and 55% of diabetic HO-1(-/-) mice had mural thrombi in the left ventricles. The increased mortality of diabetic HO-1(-/-) mice may be in part due to formation of left ventricular mural thrombi. Our data demonstrate that the absence of HO-1 renders animals more susceptible to myocardial ischemia/reperfusion damage and diabetes worsens the injury.
Diabetes 2005 Mar
PMID:Absence of heme oxygenase-1 exacerbates myocardial ischemia/reperfusion injury in diabetic mice. 1573 56

This study investigated the role of heme oxygenase (HO)-1 in the cardiac tissue injury of acute ischemia/reperfusion (I/R) in diabetic streptozotocin (STZ)-induced hyperglycemic rats. The effects of 1) hemin, an inducer of HO expression and activity, and 2) zinc protoporphyrin IX (ZnPP-IX), an inhibitor of HO activity, have also been investigated on the tissue injury by I/R and some mediators released in these circumstances. STZ hyperglycemic rats had impaired levels of HO-1 within the cardiac tissue and increased myocardial infarct size (IS) following I/R, as compared with the nondiabetic rats. In these rats, administration of hemin 4 mg/kg 18 h before I/R increases the levels of HO-1 within the tissue. However, the values of HO-1 assayed in these circumstances were significantly lower (P < 0.01) than those assayed in nondiabetic animals subjected to the same procedures; IS was much more extended (P < 0.01) than in the parent nondiabetic group. STZ hyperglycemic rats also predisposed the heart to produce high levels of the cytokines interleukin (IL)-1beta and CXCL8. Subsequent I/R further increased (P < 0.01) the cytokine production, an effect partly prevented by hemin treatment. This recovered the huge number of infiltrated polymorphonuclear (PMN) leukocytes within the cardiac tissue associated with the STZ hyperglycemic state and I/R damage.
Diabetes 2005 Mar
PMID:Hyperglycemia in streptozotocin-induced diabetic rat increases infarct size associated with low levels of myocardial HO-1 during ischemia/reperfusion. 1573 59

This study was conducted to test the hypothesis that dietary supplementation of arginine, the physiologic precursor of nitric oxide (NO), reduces fat mass in the Zucker diabetic fatty (ZDF) rat, a genetically obese animal model of type-II diabetes mellitus. Male ZDF rats, 9 wk old, were pair-fed Purina 5008 diet and received drinking water containing arginine-HCl (1.51%) or alanine (2.55%, isonitrogenous control) for 10 wk. Serum concentrations of arginine and NO(x) (oxidation products of NO) were 261 and 70% higher, respectively, in arginine-supplemented rats than in control rats. The body weights of arginine-treated rats were 6, 10, and 16% lower at wk 4, 7, and 10 after the treatment initiation, respectively, compared with control rats. Arginine supplementation reduced the weight of abdominal (retroperitoneal) and epididymal adipose tissues (45 and 25%, respectively) as well as serum concentrations of glucose (25%), triglycerides (23%), FFA (27%), homocysteine (26%), dimethylarginines (18-21%), and leptin (32%). The arginine treatment enhanced NO production (71-85%), lipolysis (22-24%), and the oxidation of glucose (34-36%) and octanoate (40-43%) in abdominal and epididymal adipose tissues. Results of the microarray analysis indicated that arginine supplementation increased adipose tissue expression of key genes responsible for fatty acid and glucose oxidation: NO synthase-1 (145%), heme oxygenase-3 (789%), AMP-activated protein kinase (123%), and peroxisome proliferator-activated receptor gamma coactivator-1alpha (500%). The induction of these genes was verified by real-time RT-PCR analysis. In sum, arginine treatment may provide a potentially novel and useful means to enhance NO synthesis and reduce fat mass in obese subjects with type-II diabetes mellitus.
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PMID:Dietary L-arginine supplementation reduces fat mass in Zucker diabetic fatty rats. 1579 23

Increased heme oxygenase (HO)-1 activity attenuates endothelial cell apoptosis and decreases superoxide anion (O2-) formation in experimental diabetes by unknown mechanisms. We examined the effect of HO-1 protein and HO activity on extracellular SOD (EC-SOD), catalase, O2-, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) levels and vascular responses to ACh in control and diabetic rats. Vascular EC-SOD and plasma catalase activities were significantly reduced in diabetic compared with nondiabetic rats (P < 0.05). Upregulation of HO-1 expression by intermittent administration of cobalt protoporphyrin, an inducer of HO-1 protein and activity, resulted in a robust increase in EC-SOD but no significant change in Cu-Zn-SOD. Administration of tin mesoporphyrin, an inhibitor of HO-1 activity, decreased EC-SOD protein. Increased HO-1 activity in diabetic rats was associated with a decrease in iNOS but increases in eNOS and plasma catalase activity. On the other hand, aortic ring segments from diabetic rats exhibited a significant reduction in vascular relaxation to ACh, which was reversed with cobalt protoporphyrin treatment. These data demonstrate that an increase in HO-1 protein and activity, i.e., CO and bilirubin production, in diabetic rats brings about a robust increase in EC-SOD, catalase, and eNOS with a concomitant increase in endothelial relaxation and a decrease in O2-. These observations in experimental diabetes suggest that the vascular cytoprotective mechanism of HO-1 against oxidative stress requires an increase in EC-SOD and catalase.
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PMID:Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes. 1582 Oct 39


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