Mitochondrial Peroxiredoxin-3 protects against hyperglycemia induced myocardial damage in Diabetic cardiomyopathy

Arkat, Silpa; Umbarkar, Prachi; Singh, Sarojini; Sitasawad, Sandhya L.

doi:10.1016/j.freeradbiomed.2016.06.019

Cited by 42 publications

(30 citation statements)

References 41 publications

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“…Thioredoxin 2 is the major mitochondrial redox regulator, and plays a very important role in alleviating cellular stress [ 28 ]. In the present study, we show that Trx2 expression is decreased in H9c2 cardiac cells treated with high glucose, which is consistent with the observation that the Trx2 expression is decreased in mitochondria isolated from STZ diabetic rats [ 29 ]. Studies show that the increased ROS emission from the mitochondrial electron transport chain in diabetes plays an essential role in cardiovascular complications [ 30 ].…”

Section: Discussionsupporting

confidence: 92%

Thioredoxin 2 Offers Protection against Mitochondrial Oxidative Stress in H9c2 Cells and against Myocardial Hypertrophy Induced by Hyperglycemia

et al. 2017

IJMS

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Mitochondrial oxidative stress is thought to be a key contributor towards the development of diabetic cardiomyopathy. Thioredoxin 2 (Trx2) is a mitochondrial antioxidant that, along with Trx reductase 2 (TrxR2) and peroxiredoxin 3 (Prx3), scavenges H2O2 and offers protection against oxidative stress. Our previous study showed that TrxR inhibitors resulted in Trx2 oxidation and increased ROS emission from mitochondria. In the present study, we observed that TrxR inhibition also impaired the contractile function of isolated heart. Our studies showed a decrease in the expression of Trx2 in the high glucose-treated H9c2 cardiac cells and myocardium of streptozotocin (STZ)-induced diabetic rats. Overexpression of Trx2 could significantly diminish high glucose-induced mitochondrial oxidative damage and improved ATP production in cultured H9c2 cells. Notably, Trx2 overexpression could suppress high glucose-induced atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression. Our studies suggest that high glucose-induced mitochondrial oxidative damage can be prevented by elevating Trx2 levels, thereby providing extensive protection to the diabetic heart.

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Section: Discussionsupporting

confidence: 92%

Thioredoxin 2 Offers Protection against Mitochondrial Oxidative Stress in H9c2 Cells and against Myocardial Hypertrophy Induced by Hyperglycemia

et al. 2017

IJMS

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“…Peroxiredoxin-3 (Prx-3) is another mitochondrial anti-oxidant, which has recently been investigated in the context of hyperglycaemia-induced cardiac dysfunction in diabetic cardiomyopathy 68 . It was found that Prx-3 levels were significantly reduced in rat H9c2 cardiac cells maintained under hyperglycaemic conditions, and also in STZ-induced diabetic rats.…”

Section: Peroxiredoxin-3mentioning

confidence: 99%

Cardiac oxidative stress in diabetes: Mechanisms and therapeutic potential

Faria

Persaud

2017

Pharmacology & Therapeutics

231

126

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Macrovascular complications of diabetes, including diabetic cardiovascular disease (CVD), occur through a number of hyperglycaemia-induced mechanisms that include generation of oxidative stress, accumulation of advanced glycation end-products (AGE) and activation of protein kinase C (PKC). Cardiac oxidative stress is associated with increased cardiac fibrosis and hypertrophy, and reduced cardiac performance and contractility, leading to severe cardiac dysfunction and potentially fatal cardiac events. It occurs under conditions of excessive synthesis of reactive oxygen species (ROS). The ensuing activation of transcription factors such as nuclear factor-κB produces inflammation, fibrosis, hypertrophy and further oxidative stress, which itself causes DNA and membrane damage. This review summarises the mechanisms that generate ROS in the diabetic heart: mitochondrial electron leakage, activity of ROS-generating enzymes such as NADPH oxidase, xanthine oxidase and 12/15 lipoxygenase, uncoupling of nitric oxide synthase, accumulation of AGEs and activation of PKC. There is interaction between many of these ROS-generating pathways, with data from a range of published studies indicating that a common upstream pathway is the interaction of AGEs with their receptor (RAGE), which further promotes ROS synthesis. Therefore, agents targeted at decreasing ROS production have been investigated for prevention or treatment of diabetic CVD through reducing oxidative stress, and this review considers some of the studies carried out with anti-oxidant therapies and the feasibility of this approach for protecting against diabetic cardiomyopathy.

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“…Multiple factors are responsible for the pathogenesis of DCM. Mounting evidence from current studies has indicated that the generation of reactive oxygen species (ROS) contributes to the progression of diabetes‐induced cardiac dysfunction . Mitochondria are critical organelles for ROS generation and energy production in cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

“…Mounting evidence from current studies has indicated that the generation of reactive oxygen species (ROS) contributes to the progression of diabetes-induced cardiac dysfunction. 4,5 Mitochondria are critical organelles for ROS generation and energy production in cardiomyocytes. Recent work has highlighted the important role of mitochondrial fusion/fission dynamics in mitochondrial homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Melatonin prevents Drp1‐mediated mitochondrial fission in diabetic hearts through SIRT1‐PGC1α pathway

Ding

Feng

Tang

et al. 2018

Journal of Pineal Research

287

205

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Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes‐induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes‐induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes‐induced cardiac dysfunction by inhibiting dynamin‐related protein 1 (Drp1)‐mediated mitochondrial fission. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin (STZ)‐induced diabetic mice, but not in SIRT1−/− diabetic mice. In high glucose‐exposed H9c2 cells, melatonin treatment increased the expression of SIRT1 and PGC‐1α and inhibited Drp1‐mediated mitochondrial fission and mitochondria‐derived superoxide production. In contrast, SIRT1 or PGC‐1α siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1‐mediated mitochondrial fission in a SIRT1/PGC‐1α‐dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC‐1α directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi‐1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes‐induced cardiac dysfunction by preventing mitochondrial fission through SIRT1‐PGC1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes.

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Mitochondrial Peroxiredoxin-3 protects against hyperglycemia induced myocardial damage in Diabetic cardiomyopathy

Cited by 42 publications

References 41 publications

Thioredoxin 2 Offers Protection against Mitochondrial Oxidative Stress in H9c2 Cells and against Myocardial Hypertrophy Induced by Hyperglycemia

Thioredoxin 2 Offers Protection against Mitochondrial Oxidative Stress in H9c2 Cells and against Myocardial Hypertrophy Induced by Hyperglycemia

Cardiac oxidative stress in diabetes: Mechanisms and therapeutic potential

Melatonin prevents Drp1‐mediated mitochondrial fission in diabetic hearts through SIRT1‐PGC1α pathway

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