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Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

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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.

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Preeclampsia plasma alters mitochondrial metabolism in plasma treated HUVEC.(a) Human umbilical vein endothelial cells were incubated with 3% plasma from women with preeclampsia, uncomplicated pregnancies and non-pregnant women for 4 hrs. Oxygen consumption rate was measured with MitoXpress fluorogenic probe. Time-resolved fluorescence of each well was then measured every 2 minutes for a total of 180 minutes. Rate of oxygen consumption was determined from the slope of fluorescence vs. time for each sample using relative fluorescence units/hour. Data are expressed as mean ± SEM. (*P < 0.05 vs normal pregnancy). Data are representative of 5 independent experiments.
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f1: Preeclampsia plasma alters mitochondrial metabolism in plasma treated HUVEC.(a) Human umbilical vein endothelial cells were incubated with 3% plasma from women with preeclampsia, uncomplicated pregnancies and non-pregnant women for 4 hrs. Oxygen consumption rate was measured with MitoXpress fluorogenic probe. Time-resolved fluorescence of each well was then measured every 2 minutes for a total of 180 minutes. Rate of oxygen consumption was determined from the slope of fluorescence vs. time for each sample using relative fluorescence units/hour. Data are expressed as mean ± SEM. (*P < 0.05 vs normal pregnancy). Data are representative of 5 independent experiments.

Mentions: The emerging role of mitochondrial dysfunction in mediating the pathogenesis of preeclampsia, led us to investigate a potential link between deleterious plasma mediators in preeclampsia and a subsequent dysregulation of mitochondrial function in HUVEC. In our first set of experiments we examined mitochondrial respiration by measuring oxygen consumption in plasma-treated HUVEC using the MitoXpress assay containing an oxygen sensitive fluorescent probe. Rates of oxygen consumption (OCR) are calculated from the changes in fluorescence signal over time using fluorescence plate reader. We established that after 4 hrs incubation of HUVEC with 3% plasma from women with preeclampsia significantly reduced OCR (40.61 ± 18.10 RFU, n = 5, P < 0.05) when compared with treatment with 3% plasma from uncomplicated pregnant (94.12 ± 34.9 RFU, n = 5) and non-pregnant women (52.12 ± 18.8, n = 5) (Fig. 1).


Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia
Preeclampsia plasma alters mitochondrial metabolism in plasma treated HUVEC.(a) Human umbilical vein endothelial cells were incubated with 3% plasma from women with preeclampsia, uncomplicated pregnancies and non-pregnant women for 4 hrs. Oxygen consumption rate was measured with MitoXpress fluorogenic probe. Time-resolved fluorescence of each well was then measured every 2 minutes for a total of 180 minutes. Rate of oxygen consumption was determined from the slope of fluorescence vs. time for each sample using relative fluorescence units/hour. Data are expressed as mean ± SEM. (*P < 0.05 vs normal pregnancy). Data are representative of 5 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Preeclampsia plasma alters mitochondrial metabolism in plasma treated HUVEC.(a) Human umbilical vein endothelial cells were incubated with 3% plasma from women with preeclampsia, uncomplicated pregnancies and non-pregnant women for 4 hrs. Oxygen consumption rate was measured with MitoXpress fluorogenic probe. Time-resolved fluorescence of each well was then measured every 2 minutes for a total of 180 minutes. Rate of oxygen consumption was determined from the slope of fluorescence vs. time for each sample using relative fluorescence units/hour. Data are expressed as mean ± SEM. (*P < 0.05 vs normal pregnancy). Data are representative of 5 independent experiments.
Mentions: The emerging role of mitochondrial dysfunction in mediating the pathogenesis of preeclampsia, led us to investigate a potential link between deleterious plasma mediators in preeclampsia and a subsequent dysregulation of mitochondrial function in HUVEC. In our first set of experiments we examined mitochondrial respiration by measuring oxygen consumption in plasma-treated HUVEC using the MitoXpress assay containing an oxygen sensitive fluorescent probe. Rates of oxygen consumption (OCR) are calculated from the changes in fluorescence signal over time using fluorescence plate reader. We established that after 4 hrs incubation of HUVEC with 3% plasma from women with preeclampsia significantly reduced OCR (40.61 ± 18.10 RFU, n = 5, P < 0.05) when compared with treatment with 3% plasma from uncomplicated pregnant (94.12 ± 34.9 RFU, n = 5) and non-pregnant women (52.12 ± 18.8, n = 5) (Fig. 1).

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