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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.


Related in: MedlinePlus

MitoTempo scavenging reduces mROS production.HUVEC were pre-treated with 5 μM MitoTempo or 5 μM NAC for 2 hrs prior to incubation with 3% plasma from women with preeclampsia for 4 hrs and mitochondrial-specific superoxide production was detected using fluorogenic MitoSox Red dye. MitoSox Red generation was quantified using Image J software. Data is the mean of 9 independent experiments and are expressed as difference in percentage pixel intensity compared to untreated ± SEM, *P < 0.05, **P < 0.01.
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f6: MitoTempo scavenging reduces mROS production.HUVEC were pre-treated with 5 μM MitoTempo or 5 μM NAC for 2 hrs prior to incubation with 3% plasma from women with preeclampsia for 4 hrs and mitochondrial-specific superoxide production was detected using fluorogenic MitoSox Red dye. MitoSox Red generation was quantified using Image J software. Data is the mean of 9 independent experiments and are expressed as difference in percentage pixel intensity compared to untreated ± SEM, *P < 0.05, **P < 0.01.

Mentions: We examined if pre-incubation with MitoTempo could scavenge the volume of mROS production in HUVEC exposed to preeclampsia plasma mediators. To elucidate the proficiency of mitochondrial-specific antioxidants, we additionally included non-mitochondrial targeted N-acetylcysteine (NAC) in our next experiments. Cells were pre-treated with 5 μM MitoTempo or 5 μM NAC for 2 hrs prior to exposure to 3% plasma from women with preeclampsia and levels of mitochondrial superoxide were detected by fluorogenic MitoSox Red dye and analysed using Image J software. Pre-treatment with MitoTempo significantly reduced mROS generation compared to untreated cells (61.23% ± 15.42% vs 100% ± 0%, n = 9, P < 0.01). Pre-treatment with non-targeted antioxidants reduced mROS production (79.73% ± 13.97% vs 100% ± 0%, n = 9, P < 0.05) but its effects are not as potent as targeted mitochondrial antioxidants (Fig. 6).


Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia
MitoTempo scavenging reduces mROS production.HUVEC were pre-treated with 5 μM MitoTempo or 5 μM NAC for 2 hrs prior to incubation with 3% plasma from women with preeclampsia for 4 hrs and mitochondrial-specific superoxide production was detected using fluorogenic MitoSox Red dye. MitoSox Red generation was quantified using Image J software. Data is the mean of 9 independent experiments and are expressed as difference in percentage pixel intensity compared to untreated ± SEM, *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: MitoTempo scavenging reduces mROS production.HUVEC were pre-treated with 5 μM MitoTempo or 5 μM NAC for 2 hrs prior to incubation with 3% plasma from women with preeclampsia for 4 hrs and mitochondrial-specific superoxide production was detected using fluorogenic MitoSox Red dye. MitoSox Red generation was quantified using Image J software. Data is the mean of 9 independent experiments and are expressed as difference in percentage pixel intensity compared to untreated ± SEM, *P < 0.05, **P < 0.01.
Mentions: We examined if pre-incubation with MitoTempo could scavenge the volume of mROS production in HUVEC exposed to preeclampsia plasma mediators. To elucidate the proficiency of mitochondrial-specific antioxidants, we additionally included non-mitochondrial targeted N-acetylcysteine (NAC) in our next experiments. Cells were pre-treated with 5 μM MitoTempo or 5 μM NAC for 2 hrs prior to exposure to 3% plasma from women with preeclampsia and levels of mitochondrial superoxide were detected by fluorogenic MitoSox Red dye and analysed using Image J software. Pre-treatment with MitoTempo significantly reduced mROS generation compared to untreated cells (61.23% ± 15.42% vs 100% ± 0%, n = 9, P < 0.01). Pre-treatment with non-targeted antioxidants reduced mROS production (79.73% ± 13.97% vs 100% ± 0%, n = 9, P < 0.05) but its effects are not as potent as targeted mitochondrial antioxidants (Fig. 6).

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