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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

Assessment of atherosclerotic lesions (aortic oil red-O staining) in apoE−/ − and apoE−/ −, SOD2+/− mice exposed to filtered air or ETS. (A) Quantification. (B) Plasma lipoprotein profiles. Abbreviations: HDL, high-density lipoprotein; IDL/LDL, intermediate-/low-density lipoprotein; VLDL, very low-density lipoprotein.*p < 0.05 compared with unexposed apoE−/ − mice. **p < 0.05 compared with exposed apoE−/ − mice. #p < 0.05 compared with unexposed apoE−/ −, SOD2+/− mice.
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f1-ehp-119-676: Assessment of atherosclerotic lesions (aortic oil red-O staining) in apoE−/ − and apoE−/ −, SOD2+/− mice exposed to filtered air or ETS. (A) Quantification. (B) Plasma lipoprotein profiles. Abbreviations: HDL, high-density lipoprotein; IDL/LDL, intermediate-/low-density lipoprotein; VLDL, very low-density lipoprotein.*p < 0.05 compared with unexposed apoE−/ − mice. **p < 0.05 compared with exposed apoE−/ − mice. #p < 0.05 compared with unexposed apoE−/ −, SOD2+/− mice.

Mentions: We then quantified the impact of decreased SOD2 activity on atherogenesis by oil red-O staining of whole aortas harvested from mice exposed to either filtered air or ETS. apoE−/ − mice with decreased SOD2 activity had significantly higher oil red-O staining compared with apoE−/ − littermates in both the unexposed and ETS-exposed groups [Figure 1A; see also Supplemental Material, Figure 2 (doi:10.1289/ehp.1002857)]. These effects were not associated with differences in cholesterol levels between or among genotypes or exposure groups (Figure 1B), consistent with the notion that elevated mitochondrial oxidative stress can increase individual susceptibility to atherogenic factors.


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

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

Assessment of atherosclerotic lesions (aortic oil red-O staining) in apoE−/ − and apoE−/ −, SOD2+/− mice exposed to filtered air or ETS. (A) Quantification. (B) Plasma lipoprotein profiles. Abbreviations: HDL, high-density lipoprotein; IDL/LDL, intermediate-/low-density lipoprotein; VLDL, very low-density lipoprotein.*p < 0.05 compared with unexposed apoE−/ − mice. **p < 0.05 compared with exposed apoE−/ − mice. #p < 0.05 compared with unexposed apoE−/ −, SOD2+/− mice.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f1-ehp-119-676: Assessment of atherosclerotic lesions (aortic oil red-O staining) in apoE−/ − and apoE−/ −, SOD2+/− mice exposed to filtered air or ETS. (A) Quantification. (B) Plasma lipoprotein profiles. Abbreviations: HDL, high-density lipoprotein; IDL/LDL, intermediate-/low-density lipoprotein; VLDL, very low-density lipoprotein.*p < 0.05 compared with unexposed apoE−/ − mice. **p < 0.05 compared with exposed apoE−/ − mice. #p < 0.05 compared with unexposed apoE−/ −, SOD2+/− mice.
Mentions: We then quantified the impact of decreased SOD2 activity on atherogenesis by oil red-O staining of whole aortas harvested from mice exposed to either filtered air or ETS. apoE−/ − mice with decreased SOD2 activity had significantly higher oil red-O staining compared with apoE−/ − littermates in both the unexposed and ETS-exposed groups [Figure 1A; see also Supplemental Material, Figure 2 (doi:10.1289/ehp.1002857)]. These effects were not associated with differences in cholesterol levels between or among genotypes or exposure groups (Figure 1B), consistent with the notion that elevated mitochondrial oxidative stress can increase individual susceptibility to atherogenic factors.

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