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

Johansen JS, Harris AK, Rychly DJ, Ergul A - Cardiovasc Diabetol (2005)

Bottom Line: Cardiovascular complications, characterized by endothelial dysfunction and accelerated atherosclerosis, are the leading cause of morbidity and mortality associated with diabetes.Overproduction and/or insufficient removal of these free radicals result in vascular dysfunction, damage to cellular proteins, membrane lipids and nucleic acids.Therefore, new strategies with classic as well as new antioxidants should be implemented in the treatment of diabetes.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Tromso, Tromso, Norway. jeajoh@student.uit.no

ABSTRACT
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.

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Current working model for the generation of reactive species and downstream targets in diabetes. Excess generation of mitochondrial ROS due to hyperglycemia initiates a vicious circle by activating stress-sensitive pathways such as NF-κB, p38 MAPK and Jak/STAT, polyol (sorbitol) and hexosamine pathways, PKC and AGEs. Enhanced production of AGEs, sorbitol and proinflammatory cytokines exerts a positive feedback on ROS and RNS synthesis and potentiates PKC-mediated vascular dysfunction by altering gene expression as well as vascular function and structure.
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Figure 2: Current working model for the generation of reactive species and downstream targets in diabetes. Excess generation of mitochondrial ROS due to hyperglycemia initiates a vicious circle by activating stress-sensitive pathways such as NF-κB, p38 MAPK and Jak/STAT, polyol (sorbitol) and hexosamine pathways, PKC and AGEs. Enhanced production of AGEs, sorbitol and proinflammatory cytokines exerts a positive feedback on ROS and RNS synthesis and potentiates PKC-mediated vascular dysfunction by altering gene expression as well as vascular function and structure.

Mentions: The mitochondrial respiratory chain is another source of nonenzymatic generation of reactive species. During the oxidative phosphorylation process, electrons are transferred from electron carriers NADH and FADH2, through four complexes in the inner mitochondrial membrane, to oxygen, generating ATP in the process [29]. Under normal conditions, •O2- is immediately eliminated by natural defense mechanisms. A recent study demonstrated that hyperglycemia-induced generation of •O2- at the mitochondrial level is the initial trigger of vicious cycle of oxidative stress in diabetes [30,31]. When endothelial cells are exposed to hyperglycemia at the levels relevant to clinical diabetes, there is increased generation of ROS and especially •O2-, which precedes the activation of four major pathways involved in the development of diabetic complications. Nishikawa and colleagues elegantly demonstrated that generation of excess pyruvate via accelerated glycolysis under hyperglycemic conditions floods the mitochondria and causes •O2- generation at the level of Complex II in the respiratory chain. What is more important is that blockade of •O2- radicals by three different approaches using either a small molecule uncoupler of mitochondrial oxidative phosphorylation (CCCP), overexpression of uncoupling protein-1 (UCP1) or overexpression of Mn-SOD, prevented changes in NF-κB as well as polyol pathway, AGE formation and PKC activity. Based on this information, it has been postulated by several groups that mitochondrial •O2- is the initiating snowball that turns oxidative stress into an avalanche in diabetes by stimulating more ROS and RNS production via downstream activation of NF-κB-mediated cytokine production, PKC and NAD(P)H oxidase (Fig. 2). Thus, inhibition of intracellular free radical formation would provide a causal therapy approach in the prevention of oxidative stress and related vascular complications in diabetes.


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

Johansen JS, Harris AK, Rychly DJ, Ergul A - Cardiovasc Diabetol (2005)

Current working model for the generation of reactive species and downstream targets in diabetes. Excess generation of mitochondrial ROS due to hyperglycemia initiates a vicious circle by activating stress-sensitive pathways such as NF-κB, p38 MAPK and Jak/STAT, polyol (sorbitol) and hexosamine pathways, PKC and AGEs. Enhanced production of AGEs, sorbitol and proinflammatory cytokines exerts a positive feedback on ROS and RNS synthesis and potentiates PKC-mediated vascular dysfunction by altering gene expression as well as vascular function and structure.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1131912&req=5

Figure 2: Current working model for the generation of reactive species and downstream targets in diabetes. Excess generation of mitochondrial ROS due to hyperglycemia initiates a vicious circle by activating stress-sensitive pathways such as NF-κB, p38 MAPK and Jak/STAT, polyol (sorbitol) and hexosamine pathways, PKC and AGEs. Enhanced production of AGEs, sorbitol and proinflammatory cytokines exerts a positive feedback on ROS and RNS synthesis and potentiates PKC-mediated vascular dysfunction by altering gene expression as well as vascular function and structure.
Mentions: The mitochondrial respiratory chain is another source of nonenzymatic generation of reactive species. During the oxidative phosphorylation process, electrons are transferred from electron carriers NADH and FADH2, through four complexes in the inner mitochondrial membrane, to oxygen, generating ATP in the process [29]. Under normal conditions, •O2- is immediately eliminated by natural defense mechanisms. A recent study demonstrated that hyperglycemia-induced generation of •O2- at the mitochondrial level is the initial trigger of vicious cycle of oxidative stress in diabetes [30,31]. When endothelial cells are exposed to hyperglycemia at the levels relevant to clinical diabetes, there is increased generation of ROS and especially •O2-, which precedes the activation of four major pathways involved in the development of diabetic complications. Nishikawa and colleagues elegantly demonstrated that generation of excess pyruvate via accelerated glycolysis under hyperglycemic conditions floods the mitochondria and causes •O2- generation at the level of Complex II in the respiratory chain. What is more important is that blockade of •O2- radicals by three different approaches using either a small molecule uncoupler of mitochondrial oxidative phosphorylation (CCCP), overexpression of uncoupling protein-1 (UCP1) or overexpression of Mn-SOD, prevented changes in NF-κB as well as polyol pathway, AGE formation and PKC activity. Based on this information, it has been postulated by several groups that mitochondrial •O2- is the initiating snowball that turns oxidative stress into an avalanche in diabetes by stimulating more ROS and RNS production via downstream activation of NF-κB-mediated cytokine production, PKC and NAD(P)H oxidase (Fig. 2). Thus, inhibition of intracellular free radical formation would provide a causal therapy approach in the prevention of oxidative stress and related vascular complications in diabetes.

Bottom Line: Cardiovascular complications, characterized by endothelial dysfunction and accelerated atherosclerosis, are the leading cause of morbidity and mortality associated with diabetes.Overproduction and/or insufficient removal of these free radicals result in vascular dysfunction, damage to cellular proteins, membrane lipids and nucleic acids.Therefore, new strategies with classic as well as new antioxidants should be implemented in the treatment of diabetes.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Tromso, Tromso, Norway. jeajoh@student.uit.no

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus