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Mitochondrial oxidative stress significantly influences atherogenic risk and cytokine-induced oxidant production.

Harrison CM, Pompilius M, Pinkerton KE, Ballinger SW - Environ. Health Perspect. (2010)

Bottom Line: We undertook this study to determine whether increased mitochondrial oxidant production affects atherosclerotic lesion development associated with CVD risk factor exposure and endothelial cell response to TNF-α.Furthermore, experiments with small interfering RNA in endothelial cells revealed that decreased SOD2 activity increased TNF-α-mediated cellular oxidant levels compared with controls.Endogenous mitochondrial oxidative stress is an important CVD risk factor that can modulate atherogenesis and cytokine-induced endothelial cell oxidant generation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama-Birmingham, Birmingham, Alabama, USA.

ABSTRACT

Background: Oxidative stress associated with cardiovascular disease (CVD) risk factors contributes to disease development. However, less is known whether specific subcellular components play a role in disease susceptibility. In this regard, it has been previously reported that vascular mitochondrial damage and dysfunction are associated with atherosclerosis. However, no studies have determined whether altered mitochondrial oxidant production directly influences atherogenic susceptibility and response in primary cells to atherogenic factors such as tumor necrosis factor-α (TNF-α).

Objectives: We undertook this study to determine whether increased mitochondrial oxidant production affects atherosclerotic lesion development associated with CVD risk factor exposure and endothelial cell response to TNF-α.

Methods: We assessed atherosclerotic lesion formation, oxidant stress, and mitochondrial DNA damage in male apolipoprotein E (apoE)- mice with normal and decreased levels of mitochondrial superoxide dismutase-2 (SOD2; apoE(-/-) and apoE(-/-), SOD2(+/-), respectively) exposed to environmental tobacco smoke or filtered air.

Results: Atherogenesis, oxidative stress, and mitochondrial damage were significantly higher in apoE(-/-), SOD2(+/-) mice than in apoE(-/-) controls. Furthermore, experiments with small interfering RNA in endothelial cells revealed that decreased SOD2 activity increased TNF-α-mediated cellular oxidant levels compared with controls.

Conclusions: Endogenous mitochondrial oxidative stress is an important CVD risk factor that can modulate atherogenesis and cytokine-induced endothelial cell oxidant generation. Consequently, CVD risk factors that induce mitochondrial damage alter cellular response to endogenous atherogenic factors, increasing disease susceptibility.

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Related in: MedlinePlus

“Healthy” mitochondrial response to cellular stimuli such as TNF-α generates functional parameters that result in normal cell function. Disease risk factors cause mitochondrial damage that changes cellular response stimuli via increased oxidants, which creates a cycle of mitochondrial ROS production and inflammation.
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f5-ehp-119-676: “Healthy” mitochondrial response to cellular stimuli such as TNF-α generates functional parameters that result in normal cell function. Disease risk factors cause mitochondrial damage that changes cellular response stimuli via increased oxidants, which creates a cycle of mitochondrial ROS production and inflammation.

Mentions: We therefore propose that mitochondrial integrity and function are important in determining individual vulnerability to common CVD risk factors such as ETS or hypercholesterolemia. Sustained mitochondrial damage (due to CVD risk factor exposure, age, etc.) influences the way cells respond to cellular stimuli by altering mitochondrial energetics and oxidant regulation. Hence, the same “dose” of a cellular stimulus, such as TNF-α (Figure 5), can produce significantly different effects between cells with “healthy” or undamaged versus damaged mitochondria. In this model, mitochondria that sustain damage via aging or environmental stressors will generate increased oxidants in response to the same “dose” of a stimuli and therefore are more prone to activate redox-sensitive kinases (e.g., IKK complex or NF-κB kinase), which in turn activate signaling cascades that can be proinflammatory. Resultant cytokines would further induce mitochondrial ROS production, creating a cycle of inflammation and mitochondrial ROS production.


Mitochondrial oxidative stress significantly influences atherogenic risk and cytokine-induced oxidant production.

Harrison CM, Pompilius M, Pinkerton KE, Ballinger SW - Environ. Health Perspect. (2010)

“Healthy” mitochondrial response to cellular stimuli such as TNF-α generates functional parameters that result in normal cell function. Disease risk factors cause mitochondrial damage that changes cellular response stimuli via increased oxidants, which creates a cycle of mitochondrial ROS production and inflammation.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3094420&req=5

f5-ehp-119-676: “Healthy” mitochondrial response to cellular stimuli such as TNF-α generates functional parameters that result in normal cell function. Disease risk factors cause mitochondrial damage that changes cellular response stimuli via increased oxidants, which creates a cycle of mitochondrial ROS production and inflammation.
Mentions: We therefore propose that mitochondrial integrity and function are important in determining individual vulnerability to common CVD risk factors such as ETS or hypercholesterolemia. Sustained mitochondrial damage (due to CVD risk factor exposure, age, etc.) influences the way cells respond to cellular stimuli by altering mitochondrial energetics and oxidant regulation. Hence, the same “dose” of a cellular stimulus, such as TNF-α (Figure 5), can produce significantly different effects between cells with “healthy” or undamaged versus damaged mitochondria. In this model, mitochondria that sustain damage via aging or environmental stressors will generate increased oxidants in response to the same “dose” of a stimuli and therefore are more prone to activate redox-sensitive kinases (e.g., IKK complex or NF-κB kinase), which in turn activate signaling cascades that can be proinflammatory. Resultant cytokines would further induce mitochondrial ROS production, creating a cycle of inflammation and mitochondrial ROS production.

Bottom Line: We undertook this study to determine whether increased mitochondrial oxidant production affects atherosclerotic lesion development associated with CVD risk factor exposure and endothelial cell response to TNF-α.Furthermore, experiments with small interfering RNA in endothelial cells revealed that decreased SOD2 activity increased TNF-α-mediated cellular oxidant levels compared with controls.Endogenous mitochondrial oxidative stress is an important CVD risk factor that can modulate atherogenesis and cytokine-induced endothelial cell oxidant generation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama-Birmingham, Birmingham, Alabama, USA.

ABSTRACT

Background: Oxidative stress associated with cardiovascular disease (CVD) risk factors contributes to disease development. However, less is known whether specific subcellular components play a role in disease susceptibility. In this regard, it has been previously reported that vascular mitochondrial damage and dysfunction are associated with atherosclerosis. However, no studies have determined whether altered mitochondrial oxidant production directly influences atherogenic susceptibility and response in primary cells to atherogenic factors such as tumor necrosis factor-α (TNF-α).

Objectives: We undertook this study to determine whether increased mitochondrial oxidant production affects atherosclerotic lesion development associated with CVD risk factor exposure and endothelial cell response to TNF-α.

Methods: We assessed atherosclerotic lesion formation, oxidant stress, and mitochondrial DNA damage in male apolipoprotein E (apoE)- mice with normal and decreased levels of mitochondrial superoxide dismutase-2 (SOD2; apoE(-/-) and apoE(-/-), SOD2(+/-), respectively) exposed to environmental tobacco smoke or filtered air.

Results: Atherogenesis, oxidative stress, and mitochondrial damage were significantly higher in apoE(-/-), SOD2(+/-) mice than in apoE(-/-) controls. Furthermore, experiments with small interfering RNA in endothelial cells revealed that decreased SOD2 activity increased TNF-α-mediated cellular oxidant levels compared with controls.

Conclusions: Endogenous mitochondrial oxidative stress is an important CVD risk factor that can modulate atherogenesis and cytokine-induced endothelial cell oxidant generation. Consequently, CVD risk factors that induce mitochondrial damage alter cellular response to endogenous atherogenic factors, increasing disease susceptibility.

Show MeSH
Related in: MedlinePlus