Antioxidative treatment prevents activation of death-receptor- and mitochondrion-dependent apoptosis in the hearts of diabetic rats

Bojunga, Jörg; Nowak, Daniel; Mitrou, Paris S.; Hoelzer, Dieter; Zeuzem, Stefan; Chow, Kai Uwe

doi:10.1007/s00125-004-1572-7

Cited by 71 publications

(63 citation statements)

References 33 publications

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“…The significant correlations of Fas-L and TNF-α with e'/a' ratio and ventricular global peak systolic strain in diabetic patients may demonstrate that apoptosis plays a role in the pathogenesis of DCM. The ability of ALA to lower Fas-L level in our study is consistent with Bojunga et al who reported that ALA decreased Fas-L gene expression in the hearts of diabetic animals and prevented the activation of death receptor signaling [41].…”

Section: Discussionsupporting

confidence: 93%

Alpha-Lipoic Acid Improves Subclinical Left Ventricular Dysfunction in Asymptomatic Patients with Type 1 Diabetes

Hegazy¹,

Tolba²,

Mostafa³

et al. 2013

Rev Diabet Stud

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■ Abstract BACKGROUND:Oxidative stress plays an important role in the development of diabetic cardiomyopathy. Alpha-lipoic acid (ALA) is a powerful antioxidant that may have a protective role in diabetic cardiac dysfunction. AIM: We investigated the possible beneficial effect of alpha-lipoic acid on diabetic left ventricular (LV) dysfunction in children and adolescents with asymptomatic type 1 diabetes (T1D). SUB-JECTS AND METHODS: Thirty T1D patients (aged 10-14) were randomized to receive insulin treatment (n = 15) or insulin plus alpha-lipoic acid 300 mg twice daily (n = 15) for four months. Age and sex matched healthy controls (n = 15) were also included. Patients were evaluated with conventional 2-dimensional echocardiographic examination (2D), pulsed tissue Doppler (PTD), and 2-dimensional longitudinal strain echocardiography (2DS) before and after therapy. Glutathione, malondialdhyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), Fas ligand (Fas-L), matrix metalloproteinase 2 (MMP-2), and troponin-I were determined and correlated to echocardiographic parameters. RESULTS: Diabetic patients had significantly lower levels of glutathione and significantly higher MDA, NO, TNF-alpha, Fas-L, MMP-2, and troponin-I levels than control subjects. The expression of transforming growth factor beta (TGF-beta) mRNA in peripheral blood mononuclear cells was also increased in diabetic patients. Significant correlations of mitral e'/a' ratio and left ventricular global peak systolic strain with glutathione, MDA, NO, TNF-alpha, and Fas-L were observed in diabetic patients. Alpha-lipoic acid significantly increased glutathione level and significantly decreased MDA, NO, TNF-alpha, Fas-L, MMP-2, troponin-I levels, and TGF-beta gene expression. Moreover, alphalipoic acid significantly increased mitral e'/a' ratio and left ventricular global peak systolic strain in diabetic patients. CONCLUSION: These findings suggest that alpha-lipoic acid may have a role in preventing the development of diabetic cardiomyopathy in type 1 diabetes.

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Section: Discussionsupporting

confidence: 93%

Alpha-Lipoic Acid Improves Subclinical Left Ventricular Dysfunction in Asymptomatic Patients with Type 1 Diabetes

Hegazy¹,

Tolba²,

Mostafa³

et al. 2013

Rev Diabet Stud

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“…Antioxidative treatment with ALA significantly suppressed apoptosis, suggesting that antioxidants may be a therapeutic option for preventing cardiovascular damage in DM in humans (Bojunga et al 2004). In accordance with these findings, we used STB as a potent antioxidant agent to reduce the ischemia-reperfusion injury of isolated diabetic hearts.…”

Section: Discussionsupporting

confidence: 61%

Ischemia-reperfusion injury of the isolated diabetic rat heart: effect of the antioxidant stobadine

Broskova

Kyseľová²,

Knézl³

2013

gpb

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Abstract. The etiology of diabetic complications is strongly associated with increased oxidative stress. The aim of the present study was to evaluate the effect of the potent antioxidant stobadine (STB) on global ischemia-reperfusion cardiac injury in the rat model of diabetes mellitus (DM). Diabetes was induced by multiple low doses of streptozotocin. The effect of STB was compared with that of a high-dose of α-lipoic acid (ALA). All experiments were performed on isolated Langendorff-perfused hearts 10 weeks after streptozotocin administration. Diabetic hearts showed to be more resistant to ischemia-reperfusion than the control hearts, as shown by the reduced number of reperfusion dysrhythmias. The effect of the therapy with ALA (100 mg/kg i.p., 5 times a week during 8 weeks) was comparable to that of STB (25 mg/kg i.p., 5 times a week during 8 weeks) resulting in lowering the heart rate and coronary flow as well as the number of serious reperfusion dysrhythmias. Though the protective effect of STB on the reperfusion-induced dysrhythmias was comparable with that of ALA, both substances failed to enhance functional recovery of the diabetic rat heart.

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“…It is interesting to note that the alteration in mitochondrial function in vitro and in vivo has been shown to correlate with the levels of activation of AKT and BcL-2 family protein (23, 40 -42). A decrease in BcL-2 family members has been suggested to contribute to apoptosis and the translocation of cytochrome c from the mitochondria to cytosol (23,41,43). Activation of AKT has been shown to augment ATP synthesis (44), promote association of hexokinase with the VDAC channel and, in so doing, promote VDAC closure, thus blocking release of cytochrome c (45).…”

Section: Discussionmentioning

confidence: 99%

“…An increase in ROS contributes to degenerative changes in mitochondrial function (13) and membrane depolarization (21). Mitochondrial ROS production associated with hyperglycemia is increased because of the lack of antioxidants, thus restoration of antioxidant levels is beneficial in decreasing mitochondrial membrane dysfunction (22,23). Abnormalities in mitochondrial transport, either through a decrease or an increase in one of the carriers, have been shown to cause an increase in superoxide anion (O 2 Ϫ ) production (24).…”

mentioning

confidence: 99%

Heme Oxygenase-1 Enhances Renal Mitochondrial Transport Carriers and Cytochrome c Oxidase Activity in Experimental Diabetes

Noia

Driesche

Palmieri

et al. 2006

Journal of Biological Chemistry

109

105

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Up-regulation of heme oxygenase (HO-1) by either cobalt protoporphyrin (CoPP) or human gene transfer improves vascular and renal function by several mechanisms, including increases in antioxidant levels and decreases in reactive oxygen species (ROS) in vascular and renal tissue. The purpose of the present study was to determine the effect of HO-1 overexpression on mitochondrial transporters, cytochrome c oxidase, and anti-apoptotic proteins in diabetic rats (streptozotocin, (STZ)-induced type 1 diabetes). Renal mitochondrial carnitine, deoxynucleotide, and ADP/ATP carriers were significantly reduced in diabetic compared with nondiabetic rats ( p < 0.05). The citrate carrier was not significantly decreased in diabetic tissue. CoPP administration produced a robust increase in carnitine, citrate, deoxynucleotide, dicarboxylate, and ADP/ATP carriers and no significant change in oxoglutarate and aspartate/ glutamate carriers. The increase in mitochondrial carriers (MCs) was associated with a significant increase in cytochrome c oxidase activity. The administration of tin mesoporphyrin (SnMP), an inhibitor of HO-1 activity, prevented the restoration of MCs in diabetic rats. Human HO-1 cDNA transfer into diabetic rats increased both HO-1 protein and activity, and restored mitochondrial ADP/ ATP and deoxynucleotide carriers. The increase in HO-1 by CoPP administration was associated with a significant increase in the phosphorylation of AKT and levels of BcL-XL proteins. These observations in experimental diabetes suggest that the cytoprotective mechanism of HO-1 against oxidative stress involves an increase in the levels of MCs and anti-apoptotic proteins as well as in cytochrome c oxidase activity.The heme-heme oxygenase (HO), 4 HO-1 and HO-2, isoforms, are viewed as having a major role in the formation of carbon monoxide (CO) and bilirubin, and in heme breakdown (1-3). The fact that HO-1 is strongly induced by its substrate, heme, and by oxidant stress, in conjunction with the robust ability of HO-1 to guard against oxidative insult (4, 5), suggests a countervailing system to oxidative stress injury. HO-1 is a regulator of endothelial cell integrity and oxidative stress (4 -6). Up-regulation of HO-1 by pharmacological agents, including cobalt protoporphyrin (CoPP), has been shown to increase superoxide dismutase and to decrease reactive oxygen species (ROS) and NAD(P)H oxidase activity in vitro and in vivo (7-9). In earlier studies, we, as well as others, have demonstrated that overexpression of the HO-1 gene in human, rabbit, and rat endothelial cells not only renders the cells resistant to agents that elicit oxidative stress but also enhances cell growth (6) and angiogenesis (10, 11) via HO-1-derived CO (12). More recently, up-regulation of HO-1 has been shown to prevent endothelial cell death and sloughing in diabetic rats (8).Mitochondrially generated ROS have been well documented in diabetes (13,14). Hyperglycemia-mediated local formation of ROS is considered to be a major contributing factor to renal and vascula...

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Antioxidative treatment prevents activation of death-receptor- and mitochondrion-dependent apoptosis in the hearts of diabetic rats

Cited by 71 publications

References 33 publications

Alpha-Lipoic Acid Improves Subclinical Left Ventricular Dysfunction in Asymptomatic Patients with Type 1 Diabetes

Alpha-Lipoic Acid Improves Subclinical Left Ventricular Dysfunction in Asymptomatic Patients with Type 1 Diabetes

Ischemia-reperfusion injury of the isolated diabetic rat heart: effect of the antioxidant stobadine

Heme Oxygenase-1 Enhances Renal Mitochondrial Transport Carriers and Cytochrome c Oxidase Activity in Experimental Diabetes

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