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Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

View Article: PubMed Central - PubMed

ABSTRACT

Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-α, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates.

No MeSH data available.


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Detection of mitochondrial-specific superoxide in plasma treated HUVEC.HUVEC were incubated with 3% plasma from women with preeclampsia, uncomplicated pregnancies and non-pregnant women for 4 hrs and mitochondrial-specific superoxide was detected using fluorogenic MitoSox Red dye. (a) Confocal microscopy of MitoSox (red fluorescence, 1st panel) and DAPI (blue fluorescence, 2nd panel) at 20X. Merged image localizes mitochondrial superoxide production (3rd panel). (b) MitoSox Red generation was quantified using Image J software. Data is the mean of 10 independent experiments and are expressed as difference in percentage pixel intensity between the study groups ± SEM. **P < 0.01.
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f3: Detection of mitochondrial-specific superoxide in plasma treated HUVEC.HUVEC were incubated with 3% plasma from women with preeclampsia, uncomplicated pregnancies and non-pregnant women for 4 hrs and mitochondrial-specific superoxide was detected using fluorogenic MitoSox Red dye. (a) Confocal microscopy of MitoSox (red fluorescence, 1st panel) and DAPI (blue fluorescence, 2nd panel) at 20X. Merged image localizes mitochondrial superoxide production (3rd panel). (b) MitoSox Red generation was quantified using Image J software. Data is the mean of 10 independent experiments and are expressed as difference in percentage pixel intensity between the study groups ± SEM. **P < 0.01.

Mentions: Excessive production of mitochondrial-ROS is intrinsically linked to mitochondrial dysfunction. To measure mitochondrial-specific superoxide production, plasma-treated cells were labelled with MitoSox Red dye and measured by fluorescent microscopy. Therefore, in our next set of experiments (Fig. 3a,b), we observed that treatment of HUVEC with 3% plasma from women with preeclampsia significantly increased mitochondrial-specific superoxide generation (191.82% ± 25%, n = 10, P <  0.05) when compared with treatment with 3% plasma from uncomplicated pregnant (127.65% ± 24%, n = 10) and non-pregnant women (100% ± 0%, n = 10) (Fig. 3b).


Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia
Detection of mitochondrial-specific superoxide in plasma treated HUVEC.HUVEC were incubated with 3% plasma from women with preeclampsia, uncomplicated pregnancies and non-pregnant women for 4 hrs and mitochondrial-specific superoxide was detected using fluorogenic MitoSox Red dye. (a) Confocal microscopy of MitoSox (red fluorescence, 1st panel) and DAPI (blue fluorescence, 2nd panel) at 20X. Merged image localizes mitochondrial superoxide production (3rd panel). (b) MitoSox Red generation was quantified using Image J software. Data is the mean of 10 independent experiments and are expressed as difference in percentage pixel intensity between the study groups ± SEM. **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015016&req=5

f3: Detection of mitochondrial-specific superoxide in plasma treated HUVEC.HUVEC were incubated with 3% plasma from women with preeclampsia, uncomplicated pregnancies and non-pregnant women for 4 hrs and mitochondrial-specific superoxide was detected using fluorogenic MitoSox Red dye. (a) Confocal microscopy of MitoSox (red fluorescence, 1st panel) and DAPI (blue fluorescence, 2nd panel) at 20X. Merged image localizes mitochondrial superoxide production (3rd panel). (b) MitoSox Red generation was quantified using Image J software. Data is the mean of 10 independent experiments and are expressed as difference in percentage pixel intensity between the study groups ± SEM. **P < 0.01.
Mentions: Excessive production of mitochondrial-ROS is intrinsically linked to mitochondrial dysfunction. To measure mitochondrial-specific superoxide production, plasma-treated cells were labelled with MitoSox Red dye and measured by fluorescent microscopy. Therefore, in our next set of experiments (Fig. 3a,b), we observed that treatment of HUVEC with 3% plasma from women with preeclampsia significantly increased mitochondrial-specific superoxide generation (191.82% ± 25%, n = 10, P <  0.05) when compared with treatment with 3% plasma from uncomplicated pregnant (127.65% ± 24%, n = 10) and non-pregnant women (100% ± 0%, n = 10) (Fig. 3b).

View Article: PubMed Central - PubMed

ABSTRACT

Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-&alpha;, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates.

No MeSH data available.


Related in: MedlinePlus