Authors: Inoguchi, Toyoshi; Nawata, Hajime

Source: Current Drug Targets, Volume 6, Number 4, June 2005 , pp. 495-501(7)

Publisher: Bentham Science Publishers

Abstract:

Both protein kinase C (PKC) activation and increased oxidative stress have been paid attention to as important causative factors for diabetic vascular complications. In this article, we show a PKC-dependent increase in oxidative stress in vascular tissues of diabetes and insulin resistant state. High glucose level and free fatty acids stimulate de novo diacylglycerol (DAG)-PKC pathway and subsequently stimulate reactive oxygen species (ROS) production through a PKC-dependent activation of NAD(P)H oxidase. Increasing evidence has also shown that NAD(P)H oxidase components are upregulated in micro- and macro- vascular tissues of animal models and patients of diabetes and obesity. It is also noted that increased intrinsic angiotensin II production may amplify such a PKC-dependent activation of NAD(P)H oxidase in diabetic vascular tissues. These mechanisms may play an important role in the diabetic vascular complications and the accelerated atherosclerosis associated with diabetes and obesity. In addition, recent reports have shown that NAD(P)H oxidases exist in pancreatic -cells and adipocytes, and this oxidase-generated ROS production may play an important role in both the progressive -cell dysfunction and the dysregulated adipocytokine production and subsequent obesity-induced metabolic syndrome. These results suggest that an NAD(P)H oxidase activation may be a useful therapeutic target for preventing diabetic vascular complications, progressive -cell dysfunction and metabolic syndrome.

Keywords: nad(p)h oxidase; oxidative stress; protein kinase c; diabetic complications; atherosclerosis; cell; adipocyte; metabolic syndrome

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389450054021927

Affiliations: 1: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyusyu University, Fukuoka 812-8582, Japan.

Publication date: 2005-06-01

More about this publication?

• Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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