Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes

He, Xiaoqing; Kan, Hong; Cai, Lu; Ma, Qiang

doi:10.1016/j.yjmcc.2008.10.007

Cited by 234 publications

(207 citation statements)

References 41 publications

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“…It is generally believed that high blood glucose promotes reactive oxygen species (ROS) production resulting in oxidative stress in cells that in turn causes damage to multiple tissues including the heart in diabetes [5][6][7][8][9]. On the other hand, the repetitive contraction and high energy expenditure of the heart expose it to excessive ROS production and make cardiomyocytes vulnerable to oxidative damage [10]. Thus, a direct toxic effect of hyperglycemia on myocardial tissues via ROS has been suggested as a critical contributor to the development of diabetic cardiomyopathy.…”

Section: Factors Influencingmentioning

confidence: 99%

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Disruption of Nrf2 Synergizes with High Glucose to Cause Heightened Myocardial Oxidative Stress and Severe Cardiomyopathy in Diabetic Mice

2013

J Diabetes Metab

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High glucose-induced oxidative stress is a major contributing mechanism to the development of diabetic cardiomyopathy. Nrf2 is an emerging critical regulator of cellular defense against oxidative damage. The role of Nrf2 in diabetic cardiomyopathy was investigated in vivo. Streptozotocin (STZ) induced diabetes in Nrf2 knockout (KO) mice that rapidly progressed to severe conditions with high mortality within two weeks of injection; whereas, in wild type (WT) mice, diabetes was less severe with no death. Severe myocardial lesions were observed in diabetic KO mice that had high, sublethal levels of blood glucose including: (a) irregular myocardial arrangements, myofibrillar discontinuation, and cell death; (b) reduced electron density, discontinuation of myocardial fibers, and mitochondrial damage; and (c) markedly reduced contractility of the cardiomyocytes to β-agonist stimulation. Parallel to severe cardiomyopathy, the diabetic KO hearts showed: (a) increased apoptosis as revealed by TUNEL and PARP1 cleavage assays; (b) infiltration of granulocytes and macrophages as well as fibrosis indicating robust inflammatory response; and (c) heightened oxidative stress as evidenced by increased levels of 8-hydroxydeoxyquanine, free malondialdehyde, and 3-nitrotyrosine. Increased oxidative stress in the KO hearts was attributed to decrease or loss of the basal and induced expression of Nrf2-dependent cytoprotective genes. Our findings demonstrate that loss of Nrf2 function synergizes with high glucose to cause heightened oxidative stress in the heart leading to severe diabetic cardiomyopathy.

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Section: Factors Influencingmentioning

confidence: 99%

“…We have previously shown that Nrf2 is critical in defense against high glucose-induced oxidative damage in cultured cardiomyocytes [10]. In this study, we analyzed the role of Nrf2 in the development of diabetic cardiomyopathy in vivo by using the Nrf2 knockout (KO) mice and streptozotocin (STZ)-induced diabetic model.…”

Section: Factors Influencingmentioning

confidence: 99%

Disruption of Nrf2 Synergizes with High Glucose to Cause Heightened Myocardial Oxidative Stress and Severe Cardiomyopathy in Diabetic Mice

2013

J Diabetes Metab

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“…Oxidative stress, an imbalance between reactive oxygen species (ROS) generation and endogenous antioxidant capacity, is triggered in cardiomyocytes by hyperglycaemia. This contributes to the development and progression of diabetic cardiomyopathy [5][6][7][8]. The superoxide-generating enzyme NADPH oxidase is considered a major source of ROS in the heart [9].…”

Section: Introductionmentioning

confidence: 99%

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

et al. 2012

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Aims/hypothesis Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.Methods Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominantnegative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed. Results Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22 phox and apoptosis signalregulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22 phox expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function. Conclusions/interpretation These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.

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“…(26) An in vitro observation of the increasing production of ROS in the presence of hyperglycemia shows an increase in apoptosis and mitochondrial injuries leading to infarction in cardiac muscles. (8) Mitochondrial injuries cause an imbalance in reductive-oxidative reactions, inhibition of electron transport in respiratory chain, and disorders in various signaling pathways. (27) Increasing ROS and oxidative stress in cardiac muscles promote cellular apoptosis and mitochondrial injuries by mitochondrial complex II inhibitor 3-nitropropionic acid.…”

Section: Nrf2 and The Effect Of Flavonoid Antioxidants On Nrf2 In Carmentioning

confidence: 99%

“…Previous studies shows that Nrf2 plays an important role in the in vitro protection of cardiac muscle cells from injuries and death caused by oxidative stress induced by hyperglycemia. (8) In another study, rats which have their Nrf2 removed show more severe cardiac muscle injuries than those whose Nrf2 are intact after induction with streptozotocin (STZ). (9) With the discovery of the important effect of Nrf2 in reducing oxidative stress, a DM therapy targeting this system needs to be developed.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Factor Erythroid 2-related Factor 2 (Nrf2) as A Therapeutical Target in Type-2 Diabetes Mellitus: A Review

Hendrawati

2017

Indones Biomed J

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BACKGROUND: Increasing free radicals and oxidative stress due to chronic hyperglycemia in type-2 diabetes mellitus (DM) promotes the activity of endogenic antioxidative genes. Nuclear factor erythroid 2-related factor 2 (Nrf2) expression and activity are important to regulate the production of endogenic antioxidative enzymes.CONTENT: Normally, Nrf2 is bound by protein Kelchlike ECH-associated protein-1 (Keap1) in the cytosol. Stimulation from oxidative stress causes the release of Nrf2 from Keap1. When activated, Nrf2 enters the nucleus and activates the antioxidant response element (ARE). This will further increase the production of antioxidative enzymes, such as catalase, nitrite oxydase and heme oxygenase-1. The discovery of oxidative stress, as the cause of complications in DM, gives rise to the idea of developing a treatment which can increase the expression and activity of Nrf2, one of which is a flavonoid antioxidant.SUMMARY: Currently, nuclear factor erythroid 2-related factor 2 is an important target in the therapy of DM.KEYWORDS: Nrf2, type-2 diabetes mellitus, endogenic antioxidative enzymes, oxidative stress, antioxidants

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Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes

Cited by 234 publications

References 41 publications

Disruption of Nrf2 Synergizes with High Glucose to Cause Heightened Myocardial Oxidative Stress and Severe Cardiomyopathy in Diabetic Mice

Disruption of Nrf2 Synergizes with High Glucose to Cause Heightened Myocardial Oxidative Stress and Severe Cardiomyopathy in Diabetic Mice

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

Nuclear Factor Erythroid 2-related Factor 2 (Nrf2) as A Therapeutical Target in Type-2 Diabetes Mellitus: A Review

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