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Hyperglycemia and endothelial dysfunction in atherosclerosis: lessons from type 1 diabetes.

Funk SD, Yurdagul A, Orr AW - Int J Vasc Med (2012)

Bottom Line: Some of this confusion derives from studies in type 2 diabetics where multiple components of metabolic syndrome show proatherosclerotic effects independent of underlying diabetes.Endothelial cell biology plays a central role in atherosclerotic plaque formation regulating vessel permeability, inflammation, and thrombosis.The current paper highlights the mechanisms by which hyperglycemia affects endothelial cell biology to promote plaque formation.

View Article: PubMed Central - PubMed

Affiliation: Departments of Cell Biology and Anatomy and Pathology, LSU Health Sciences Center, Shreveport, LA 71130, USA.

ABSTRACT
A clear relationship between diabetes and cardiovascular disease has been established for decades. Despite this, the mechanisms by which diabetes contributes to plaque formation remain in question. Some of this confusion derives from studies in type 2 diabetics where multiple components of metabolic syndrome show proatherosclerotic effects independent of underlying diabetes. However, the hyperglycemia that defines the diabetic condition independently affects atherogenesis in cell culture systems, animal models, and human patients. Endothelial cell biology plays a central role in atherosclerotic plaque formation regulating vessel permeability, inflammation, and thrombosis. The current paper highlights the mechanisms by which hyperglycemia affects endothelial cell biology to promote plaque formation.

No MeSH data available.


Related in: MedlinePlus

Hyperglycemia-induced endothelial dysfunction and activation. (a) Hyperglycemia induces metabolic dysfunction through mitochondrial production of superoxide, resulting in PARP activation and subsequent altered glycolytic flux to enhance diacylglycerol production (DAG), methylglyoxal production, and hexosamine and polyol pathway activity. (b) Hyperglycemia-induced oxidative stress is further enhanced by metabolic overproduction of DAG and decreases in NADH+/reduced glutathione (GSH), as well as stimulation of the RAGE receptor. Oxidative stress reduces protective mediators (NO bioavailability) and enhances inflammatory transcription factor (NF-κB) activation resulting in inflammatory gene expression and leukocyte recruitment.
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fig3: Hyperglycemia-induced endothelial dysfunction and activation. (a) Hyperglycemia induces metabolic dysfunction through mitochondrial production of superoxide, resulting in PARP activation and subsequent altered glycolytic flux to enhance diacylglycerol production (DAG), methylglyoxal production, and hexosamine and polyol pathway activity. (b) Hyperglycemia-induced oxidative stress is further enhanced by metabolic overproduction of DAG and decreases in NADH+/reduced glutathione (GSH), as well as stimulation of the RAGE receptor. Oxidative stress reduces protective mediators (NO bioavailability) and enhances inflammatory transcription factor (NF-κB) activation resulting in inflammatory gene expression and leukocyte recruitment.

Mentions: Hyperglycemia stimulates cellular ROS production by four major sources including direct glucose autooxidation [111], mitochondrial superoxide production [112], eNOS uncoupling [113], and AGE-dependent NADPH oxidase activation (Figure 3(a)) [72, 73]. Glucose autooxidation and mitochondrial superoxide are likely to be the initial contributors to ROS-mediated dysfunction elicited by hyperglycemia [72]. Trace amounts of free metals catalyze glucose auto-oxidation resulting in systemic oxidant stress [114]. Glucose oxidation during glycolysis produces ROS that are generally held in check by the cell's antioxidant defenses, including superoxide dismutase (SOD), thioredoxin, glutathione peroxidase (GP), and catalase [115]. However, these systems become overloaded during hyperglycemia. Whereas many cells downregulate glucose transporters (GLUTs) in response to hyperglycemia, endothelial cells retain expression of non-insulin-dependent GLUTs allowing intracellular glucose to rise concomitantly with extracellular glucose concentrations (Figure 3(a)) [116]. Enhanced glycolytic oxidation and the disruption of the mitochondrial electron transport chain promoting electron shuttling into molecular oxygen stimulates oxidant stress. eNOS uncoupling in response to ROS production further perpetuates oxidant stress under hyperglycemic conditions (Figure 3(b)) [117]. During chronic hyperglycemia, AGE production contributes to ROS production through receptor-mediated NADPH oxidase activation (Figure 3(b)). It should be noted however, that ROS production through distinct cellular sources (NADPH oxidase, mitochondria) can lead to ROS production at secondary sites [72, 118], and the relative contributions of each source are likely to fluctuate with disease state and control (hyperglycemic spikes versus AGEs).


Hyperglycemia and endothelial dysfunction in atherosclerosis: lessons from type 1 diabetes.

Funk SD, Yurdagul A, Orr AW - Int J Vasc Med (2012)

Hyperglycemia-induced endothelial dysfunction and activation. (a) Hyperglycemia induces metabolic dysfunction through mitochondrial production of superoxide, resulting in PARP activation and subsequent altered glycolytic flux to enhance diacylglycerol production (DAG), methylglyoxal production, and hexosamine and polyol pathway activity. (b) Hyperglycemia-induced oxidative stress is further enhanced by metabolic overproduction of DAG and decreases in NADH+/reduced glutathione (GSH), as well as stimulation of the RAGE receptor. Oxidative stress reduces protective mediators (NO bioavailability) and enhances inflammatory transcription factor (NF-κB) activation resulting in inflammatory gene expression and leukocyte recruitment.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3303762&req=5

fig3: Hyperglycemia-induced endothelial dysfunction and activation. (a) Hyperglycemia induces metabolic dysfunction through mitochondrial production of superoxide, resulting in PARP activation and subsequent altered glycolytic flux to enhance diacylglycerol production (DAG), methylglyoxal production, and hexosamine and polyol pathway activity. (b) Hyperglycemia-induced oxidative stress is further enhanced by metabolic overproduction of DAG and decreases in NADH+/reduced glutathione (GSH), as well as stimulation of the RAGE receptor. Oxidative stress reduces protective mediators (NO bioavailability) and enhances inflammatory transcription factor (NF-κB) activation resulting in inflammatory gene expression and leukocyte recruitment.
Mentions: Hyperglycemia stimulates cellular ROS production by four major sources including direct glucose autooxidation [111], mitochondrial superoxide production [112], eNOS uncoupling [113], and AGE-dependent NADPH oxidase activation (Figure 3(a)) [72, 73]. Glucose autooxidation and mitochondrial superoxide are likely to be the initial contributors to ROS-mediated dysfunction elicited by hyperglycemia [72]. Trace amounts of free metals catalyze glucose auto-oxidation resulting in systemic oxidant stress [114]. Glucose oxidation during glycolysis produces ROS that are generally held in check by the cell's antioxidant defenses, including superoxide dismutase (SOD), thioredoxin, glutathione peroxidase (GP), and catalase [115]. However, these systems become overloaded during hyperglycemia. Whereas many cells downregulate glucose transporters (GLUTs) in response to hyperglycemia, endothelial cells retain expression of non-insulin-dependent GLUTs allowing intracellular glucose to rise concomitantly with extracellular glucose concentrations (Figure 3(a)) [116]. Enhanced glycolytic oxidation and the disruption of the mitochondrial electron transport chain promoting electron shuttling into molecular oxygen stimulates oxidant stress. eNOS uncoupling in response to ROS production further perpetuates oxidant stress under hyperglycemic conditions (Figure 3(b)) [117]. During chronic hyperglycemia, AGE production contributes to ROS production through receptor-mediated NADPH oxidase activation (Figure 3(b)). It should be noted however, that ROS production through distinct cellular sources (NADPH oxidase, mitochondria) can lead to ROS production at secondary sites [72, 118], and the relative contributions of each source are likely to fluctuate with disease state and control (hyperglycemic spikes versus AGEs).

Bottom Line: Some of this confusion derives from studies in type 2 diabetics where multiple components of metabolic syndrome show proatherosclerotic effects independent of underlying diabetes.Endothelial cell biology plays a central role in atherosclerotic plaque formation regulating vessel permeability, inflammation, and thrombosis.The current paper highlights the mechanisms by which hyperglycemia affects endothelial cell biology to promote plaque formation.

View Article: PubMed Central - PubMed

Affiliation: Departments of Cell Biology and Anatomy and Pathology, LSU Health Sciences Center, Shreveport, LA 71130, USA.

ABSTRACT
A clear relationship between diabetes and cardiovascular disease has been established for decades. Despite this, the mechanisms by which diabetes contributes to plaque formation remain in question. Some of this confusion derives from studies in type 2 diabetics where multiple components of metabolic syndrome show proatherosclerotic effects independent of underlying diabetes. However, the hyperglycemia that defines the diabetic condition independently affects atherogenesis in cell culture systems, animal models, and human patients. Endothelial cell biology plays a central role in atherosclerotic plaque formation regulating vessel permeability, inflammation, and thrombosis. The current paper highlights the mechanisms by which hyperglycemia affects endothelial cell biology to promote plaque formation.

No MeSH data available.


Related in: MedlinePlus