Hyperglycemia in Streptozotocin-Induced Diabetic Rat Increases Infarct Size Associated With Low Levels of Myocardial HO-1 During Ischemia/Reperfusion

Filippo, Clara Di; Marfella, Raffaele; Cuzzocrea, Salvatore; Piegari, Elena; Petronella, Pasquale; Giugliano, Dario; Rossi, Francesco; D’Amico, Michele

doi:10.2337/diabetes.54.3.803

Cited by 121 publications

(106 citation statements)

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“…CONCLUSIONS -Decreased HO-1 expression has been shown in humans and experimental animals with diabetes (11,12), and an inverse relationship between the HO-1 activity and vascular complications associated with diabetes was demonstrated (13). In line with these findings, our previous study (4) revealed that the length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients.…”

Section: Discussionsupporting

confidence: 75%

Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients

et al. 2008

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OBJECTIVE -Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeats in the promoter of human HO-1 gene has been shown to modulate gene transcription. The aim of this study was to assess the association of the length of (GT) n repeats in the HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD).RESEARCH DESIGN AND METHODS -We screened the allelic frequencies of (GT) n repeats in the HO-1 gene promoter in 986 unrelated individuals who underwent coronary angiography. Serum bilirubin and markers of iron status were evaluated.RESULTS -The distribution of numbers of (GT) n repeats was divided into two subclasses: class S included shorter (Ͻ27) repeats, and class L included longer (Ն27) repeats. Among those with diabetes, subjects with the L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70 Ϯ 0.22 vs. 0.81 Ϯ 0.24 mg/dl, P ϭ 0.001) and higher serum ferritin values (4.76 Ϯ 0.72 vs. 4.28 Ϯ 1.05 g/l for log ferritin, P ϭ 0.001). Compared with those carrying the S allele, diabetic subjects with the L/L genotype had an almost threefold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, [95% CI 1.22-6.47], P ϭ 0.015). With adjustment for both serum bilirubin and ferritin, the effect of HO-1 promoter polymorphism on susceptibility to CAD disappeared.CONCLUSIONS -Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients, and this effect might be conveyed through its influence on serum bilirubin and ferritin.

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Section: Discussionsupporting

confidence: 75%

Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients

et al. 2008

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“…Studies on experimental diabetes also revealed lower levels of HO-1 expression and HO activity in streptozotocin-induced diabetic rats com- pared with nondiabetic controls (32,33). In the present study, we did not observe significant changes in HO-1 and HO-2 protein expression along with aging process in NOD mice.…”

Section: Discussionmentioning

confidence: 33%

Systemic Expression of Heme Oxygenase-1 Ameliorates Type 1 Diabetes in NOD Mice

Lin

Chiang

et al. 2007

Diabetes

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Heme oxygenase-1 (HO-1) is an enzyme with potent immunoregulatory capacity. To evaluate the effect of HO-1 on autoimmune diabetes, female NOD mice at 9 weeks of age received a single intravenous injection of a recombinant adeno-associated virus bearing HO-1 gene (AAV-HO-1; 0.5 ؋ 10 10 -2.5 ؋ 10 10 viruses/mouse). In a dose-dependent manner, HO-1 transduction reduced destructive insulitis and the incidence of overt diabetes examined over a 15-week period. HO-1-mediated protection was associated with a lower type 1 T-helper cell (Th1)-mediated response. Adaptive transfer experiments in NOD.scid mice demonstrated that splenocytes isolated from AAV-HO-1-treated mice were less diabetogenic. Flow cytometry analysis revealed no significant difference in the percentages of CD4 ؉ CD25 ؉ regulatory T-cells between saline-treated and AAV-HO-1-treated groups. However, the CD11c ؉ major histocompatibility complex II ؉ dendritic cell population was much lower in the AAV-HO-1-treated group. A similar protective effect against diabetes was observed in NOD mice subjected to carbon monoxide (CO) gas (250 ppm CO for 2 h, twice per week). These data suggest that HO-1 slows the progression to overt diabetes in pre-diabetic NOD mice by downregulating the phenotypic maturity of dendritic cells and Th1 effector function. CO appears to mediate at least partly the beneficial effect of HO-1 in this disease setting. Diabetes 56:1240-1247, 2007 T ype 1 diabetes is a chronic autoimmune disorder characterized by the progressive destruction of pancreatic insulin-producing ␤-cells (1). Studies on NOD mice, which spontaneously develop type 1 diabetes with features similar to the human disease, have demonstrated that the disease is initiated by infiltration of antigen-presenting cells (APCs), particularly dendritic cells, into pancreatic islets followed by recruitment of T-and B-cells (2,3). In these mice, insulitis appears around 3-4 weeks of age and is well established by 10 weeks without clinical symptoms. The progression to overt diabetes occurs in 80% of female mice by 30 weeks of age. Evidence suggests that ␤-cell destruction is mediated primarily by a skewed type 1 T helper cell (Th1)-mediated response and the production of proinflammatory cytokines (4). How the biased Th1 phenotype and the progression to destructive insulitis are regulated over the course of type 1 diabetes development is not fully understood. Nevertheless, it is well documented that full activation of naive T-cells requires presentation of antigen in the context of the major histocompatibility complex (MHC) II complex and costimulatory signals from mature dendritic cells (5-7). Dendritic cells from NOD mice have been shown to exhibit enhanced APC function and abnormally high costimulatory and Th1-inducing abilities (8 -10). Furthermore, increasing evidence suggests that the autoimmune process is caused by the failure of immunosuppressive mechanisms (11-13). A naturally occurring CD4 ϩ CD25 ϩ regulatory T (Treg) cell population with suppressive function has been shown to ...

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“…13,14,27,28) Under normal condition, pathophysiological stimuli that increase oxidative stress can up-regulate certain protective molecules such as heme oxygenase (HO)-1, a cytoprotective heme-degrading enzyme, and antioxidants including SOD, catalase and metallothionein in the heart. 40) It was found that HO-1 expression was increased in the mouse hearts subjected to I/R, but I/R-induced up-regulation of HO-1 expression in non-diabetic mice was absent in diabetic hearts.…”

Section: Discussionmentioning

confidence: 99%

“…Subjects with diabetes experience an increased risk of cardiac infarction and cardiac failure compared to non-diabetic age-matched individuals. 13,14,27,28) We and other groups have confirmed that supplementation or over-expression of FGFs can protect the heart from ischemia/reperfusion (I/R)-induced injury in animal models and in patients. [29][30][31][32][33][34][35][36] However, whether FGFs can protect diabetic heart from I/Rinduced injury has not been addressed.…”

mentioning

confidence: 98%

“…[4][5][6][7][8][9][10][11][12] Diabetes was found to impair endogenous defense mechanisms in the tissues. [13][14][15][16] For instance, diabetes inhibited the expression, and also induced glycosylation of several growth factors, including endogenous FGF. [17][18][19][20][21] Decreased serum levels of bFGF with other growth factors were found to increase cardiovascular events (including infarction, revascularization, stroke and peripheral vascular disease) in diabetic patients.…”

mentioning

confidence: 99%

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Cardiac Protection by Basic Fibroblast Growth Factor from Ischemia/Reperfusion-Induced Injury in Diabetic Rats

Xiao

Lin

et al. 2010

Biological & Pharmaceutical Bulletin

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Diabetes impairs the expression and function of endogenous growth factors, leading to increased cardiovascular events in diabetic patients. Supplementation of fibroblast growth factors (FGFs) protected the heart from ischemia/reperfusion (I/R)-induced injury in animal models. However, it has not yet been tested in diabetic heart. The present study was thus to clarify whether basic fibroblast growth factor (bFGF) could protect the heart from I/R-induced damage under diabetic conditions using a rat model. Male Sprague Dawley rats were used to induce diabetes by intraperitoneal injection of streptozotocin. Eight weeks later, I/R injury was generated in diabetic rats and age-matched non-diabetic rats. All I/R rats were administrated bFGF or saline through intramyocardial injection. Seven days after I/R, cardiac infarction, structural changes, cell death and blood vessel density, serum malondialdehyde (MDA) and cardiac enzyme lactate dehydrogenase (LDH) were examined. We found that I/R induced significant increases in the cardiac infarction, blood MDA contents and LDH activities, and the expression of caspase-3. Treatment of I/R rats with bFGF simultaneously with reperfusion significantly attenuated I/Rinduced pathological changes, along with a significant increase in the cardiac blood vessel density in both diabetic and non-diabetic rates. The protective effects of bFGF on I/R-induced cardiac injury in diabetic group are less than those in non-diabetic group. The results indicated that bFGF provide a protection of the heart against I/R-induced oxidative damage, cell death and infarction under diabetic conditions.

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Hyperglycemia in Streptozotocin-Induced Diabetic Rat Increases Infarct Size Associated With Low Levels of Myocardial HO-1 During Ischemia/Reperfusion

Cited by 121 publications

References 40 publications

Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients

Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients

Systemic Expression of Heme Oxygenase-1 Ameliorates Type 1 Diabetes in NOD Mice

Cardiac Protection by Basic Fibroblast Growth Factor from Ischemia/Reperfusion-Induced Injury in Diabetic Rats

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