Oxidative stress and diabetic complications.

Abstract

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.

• Authors: Ferdinando Giacco, Michael Brownlee
• Journal: Circulation research (Circ Res) Vol. 107 Issue 9 Pg. 1058-70 (Oct 29 2010) ISSN: 1524-4571 [Electronic] United States
• PMID: 21030723 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Reactive Oxygen Species

Topics

• Animals
• Atherosclerosis (etiology, metabolism)
• Cardiomyopathies (etiology, metabolism)
• Diabetes Complications (etiology, metabolism)
• Humans
• Hyperglycemia (complications, metabolism)
• Microvessels (metabolism)
• Oxidative Stress (physiology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (physiology)