Diabetic Atherosclerosis - Pathology

Reactive Oxygen Species (ROS) - updated: 15 March 2008

Cellular mechanisms and treatment of diabetes vascular complications converge on reactive oxygen species

Curr Hypertens Rep. 2005 Apr;7(2):148-54

Whiteside CI.

High glucose activates a myriad of signaling and gene expression pathways in non-insulin-dependent target cells causing diabetes complications. One of the earliest responses to high glucose by vascular cells is the generation of reactive oxygen species (ROS) that act directly on intracellular proteins and DNA, or indirectly as second messengers, transforming these cells into disease phenotypes. ROS are produced by mitochondria and/or NADPH oxidase in all target cells exposed to high glucose studied to date. Reports using cell cultures and diabetic animal models indicate that inhibition of ROS generation prevents the amplification of signaling and gene expression that are implicated in vascular complications. These models convincingly demonstrate that maneuvers preventing ROS production attenuate or completely abrogate early micro- and macrovascular end-organ damage of diabetes, including nephropathy, retinopathy, and large-vessel atherosclerosis. Attention now turns to the development of more effective antioxidants that could be used in clinical trials in the prevention and treatment of diabetes complications.

Publication Types:

• Review

A possible target of antioxidative therapy for diabetic vascular complications-vascular NAD(P)H oxidase

Curr Med Chem. 2003 Sep;10(17):1759-64

Inoguchi T, Tsubouchi H, Etoh T, Kakimoto M, Sonta T, Utsumi H, Sumimoto H, Yu HY, Sonoda N, Inuo M, Sato N, Sekiguchi N, Kobayashi K, Nawata H.

A growing body of evidence has shown that oxidative stress may be involved in the development of vascular complications associated with diabetes. However, the molecular mechanism for increased reactive oxygen species (ROS) production in diabetes remains uncertain. Among various possible mechanisms, attention have increasingly been paid to NAD(P)H oxidase as the most important source of ROS production in vascular cells. High glucose level stimulates ROS production through protein kinase C (PKC)-dependent activation of vascular NAD(P)H oxidase. Furthermore, the expression of NAD(P)H oxidase components is increased in micro- and macrovascular tissues of diabetic animals in association with various functional disorders and histochemical abnormalities. These results suggest that vascular NAD(P)H oxidase-driven ROS production may contribute to the onset or development of diabetic micro- or macrovascular complications. In this point of view, the possible new strategy of antioxidative therapy for diabetic vascular complications is discussed in this review.

Publication Types:

• Review

Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice

Cardiovasc Diabetol. 2005 Apr 29;4(1):5

Johansen JS, Harris AK, Rychly DJ, Ergul A.

Cardiovascular complications, characterized by endothelial dysfunction and accelerated atherosclerosis, are the leading cause of morbidity and mortality associated with diabetes. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Overproduction and/or insufficient removal of these free radicals result in vascular dysfunction, damage to cellular proteins, membrane lipids and nucleic acids. Despite overwhelming evidence on the damaging consequences of oxidative stress and its role in experimental diabetes, large scale clinical trials with classic antioxidants failed to demonstrate any benefit for diabetic patients. As our understanding of the mechanisms of free radical generation evolves, it is becoming clear that rather than merely scavenging reactive radicals, a more comprehensive approach aimed at preventing the generation of these reactive species as well as scavenging may prove more beneficial. Therefore, new strategies with classic as well as new antioxidants should be implemented in the treatment of diabetes.

Publication Types:

• Review

The role of free radicals, oxidative stress and antioxidant systems in diabetic vascular disease

Bratisl Lek Listy. 2000;101(10):541-51

Jakus V.

Recent experimental findings suggest that overproduction of reactive oxygen and nitrogen species (ROS/RNS), lowered antioxidant defense and alterations of enzymatic pathways in humans with poorly controlled diabetes mellitus can contribute to endothelial, vascular and neurovascular dysfunction. Over the past decade, there has been substantial interest in oxidative stress and its potential role in diabetogenesis, development of diabetic complications, atherosclerosis and associated cardiovascular disease. Consequences of oxidative stress are damage to DNA, lipids, proteins, disruption in cellular homeostasis and accumulation of damaged molecules. This review summarizes recent knowledge on the pathomechanism of ROS/RNS in vascular oxidative stress and Maillard reactions. Evidence suggests that Maillard reactions act as amplifier of oxidative damage in aging and diabetes. Furthermore, results of experimental observations with antioxidant systems and antioxidant pharmacotherapy in the treatment of diabetes mellitus are discussed. These data indicate that the targeting therapy to specific macromolecules, tissues and organs of diabetics by specific antioxidants or combined drug preparates could become a relevant adjuvant pharmacotherapy with improved glycaemic control, blood pressure control and management of dyslipidemia for the treatment or prevention of progression of micro- and macrovascular diabetic complications. Supplementation with antioxidants as a promising complementary treatment can exert beneficial effects in diabetes. Some antidiabetic drugs may have antioxidant properties independently of their main role on glycaemia control. Therapeutic potential of inhibitors of AGEs formation for delaying of diabetic complications is now intensively studied in several laboratories. Furthermore, for functional outcomes of the intervention with antioxidants is also important development of accurate and sensitive methods for early detection of oxidative damage in diabetes.

Publication Types:

• Review

Role of vascular reactive oxygen species in development of vascular abnormalities in diabetes

Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S65-70. Epub 2007 Apr 27

Son SM.

Macrovascular and microvascular diseases are currently the principal causes of morbidity and mortality in patients with diabetes. Oxidative stress has been postulated to be a major contributor to the pathogenesis of these events. There is considerable evidence that many biochemical pathways adversely affected by hyperglycemia and other substances that are found at elevated levels in diabetic patients are associated with the generation of reactive oxygen species, ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensation by the endogenous antioxidant defense network, increased oxidative stress leads to the activation of stress-sensitive intracellular signaling pathways and the formation of gene products that cause cellular damage and contribute to the late complications of diabetes. It has recently been suggested that diabetic subjects with vascular complications may have a defective cellular antioxidant response against the oxidative stress generated by hyperglycemia. This raises the concept that antioxidant therapy may be of great interest in these patients. Although our understanding of how hyperglycemia-induced oxidative stress ultimately leads to tissue damage has advanced considerably in recent years, effective therapeutic strategies to prevent or delay the development of this damage remain limited. Thus, further investigations of therapeutic interventions to prevent or delay the progression of diabetic vascular complications are needed.

Publication Types:

• Review

Publication Types:

• Review