Impact of mitochondrial ROS production on diabetic vascular complications

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Abstract

Vascular complications are the leading cause of morbidity and mortality in patients with diabetes. Four main molecular mechanisms have been implicated in glucose-mediated vascular disease. There are: glucose-induced activation of protein kinase C (PKC) isoforms; increased formation of glucose-derived advanced glycation end-products (AGE); increased glucose flux through the aldose reductase pathway; and increased production of reactive oxygen species (ROS). Here we demonstrate that hyperglycemia-induced production of ROS is abrogated by inhibitors of mitochondrial metabolism, or by overexpression of uncoupling protein-1 or manganese superoxide dismutase. Normalization of mitochondrial ROS production by each of these agents prevents glucose-induced activation of PKC, formation of AGE, and accumulation of sorbitol in bovine vascular endothelial cells. We also claim that 8-hydroxydeoxyguanosine, which represents mitochondrial oxidative damage was elevated in patients with either retinopathy, albuminuria or increased intima-media thickness of carotid arteries. These results suggest that hyperglycemia induces mitochondrial ROS production, and which can associate to the pathogenesis of diabetic vascular complications.

Introduction

Diabetes is characterized by chronic hyperglycemia and the development of diabetic microvascular and macrovascular complications. The outcome of the Diabetes Control and Complication Trial [1], Kumamoto Study [2], [3], [4] and UK Prospective Diabetes Study [5] appears to have effectively resolved the long debate over whether chronic hyperglycemia is an important cause of diabetic vascular complications, but it is still unclear the mechanisms through which hyperglycemia acts as a crucial risk factor for vascular complications. Four seemingly independent mechanisms are involved in the pathogenesis of diabetic complications: glucose-induced activation of protein kinase C (PKC) isoforms [6], [7]; increased formation of glucose-derived advanced glycation end-products [8], [9], [10], [11]; increased polyol pathway [12]; and increased production of reactive oxygen species (ROS) [13]. There is no unifying hypothesis linking these four mechanisms together. However, we recently demonstrated that hyperglycemia could increase ROS production from mitochondrial electron transport chain, and we proposed that this mitochondrial ROS production could be a key event in the development of diabetic complications.

Here we demonstrate the mechanism of hyperglycemia-induced damage by mitochondrial ROS overproduction, and we also show the relationship between mitochondrial ROS production and diabetes complications in type 2 diabetes patients.

Section snippets

Role of mitochondrial electron transport chain in hyperglycemia-induced ROS production

Mitochondria are central in the traffic of cellular metabolism and transport. The most universal and critical mitochondrial function is oxidative phosphorylation. The overall system of oxidative phosphorylation includes five large multienzyme complexes, designated as complexes I, II, III, IV and ATP synthase (Fig. 1). This mitochondrial respiratory system is thought to be the major source of ROS under normal physiological condition. There are two main sites of superoxide generation in this

A single element linking hyperglycemia-induced damage

Three main hypotheses about how hyperglycemia causes diabetic complications have generated a large amount of data, as well as several clinical trials based on specific inhibitors of these mechanisms. Three hypotheses are: activation of PKC; increased AGE formation; and activation of polyol pathway. Until recently, there was no unifying hypothesis linking these four mechanisms. Therefore, we examined the effects of mitochondrial ROS inhibitor on these three independent biochemical pathways.

Mitochondrial ROS production in type 2 diabetic patients

It is still unclear whether mitochondrial ROS production associates with the progression of diabetic complications in type 2 diabetic patients. Therefore, to determine the role of mitochondrial ROS production in type 2 diabetic patients, the relationship between 8-hydroxydeoxyguanosine (8-OHdG) and the severity of diabetic complications were examined. 8-OHdG is a product of oxidative DNA damage following specific enzymatic cleavage after 8-hydroxylation of the guanine base (Fig. 4). As

Relationship between glycemic control and mitochondrial ROS production

Kumamoto Study was a randomized clinical trial designed to compare intensive insulin therapy (MIT) using multiple insulin injections with conventional insulin injection therapy (CIT) to evaluate the effects of glycemic control on the development and progression of microvascular complications in Japanese patients with type 2 diabetes. We have already reported that intensive glycemic control could delay the onset and progression of early stages of diabetic microvascular complications [2], [3], [4]

Conclusion

The main purpose of treatment in diabetes patients must be to prevent the onset and progression of chronic diabetic vascular complications, and hyperglycemia must be the primary initiating factor in the pathogenesis of diabetic complications. Here we demonstrated that hyperglycemia-induced mitochondrial ROS production could be a key event in the development of diabetic complications. The present study must provide a conceptual framework for future research and drug discovery, which targets

Acknowledgements

The authors thank Dr. M. Brownlee (Albert Einstein College of Medicine, Bronx, NY) for providing the rat UCP-1 and human MnSOD adenoviral vectors.

This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Japan (No. 18590995 to T.N.), and by grants from Takeda Science Foundation (to T.N.).

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