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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.

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Effect of MitoTempo on inflammatory and redox signalling markers in HUVEC.HUVEC were pre-treated with 5 μM MitoTempo for 2 hrs prior to exposure to 100 ng/ml LPS for 24 hrs and gene expression of inflammatory markers were quantified by real-time PCR. (a) Gene expression of inflammatory markers TNF-α and endothelin-1 respectively was determined in LPS-stimulated HUVEC. Cells were pre-treated with 5 μM MitoTempo for 2 hrs prior to exposure to 200 μM H2O2 for 24hrs and gene expression of redox markers were quantified by real-time PCR. (b) Gene expression of redox signalling mediators, SOD1, SOD2, HO-1, UCP-1and TLR-9 respectively were determined in HUVEC following oxidative stress insult. The amounts of amplified products are expressed relative to geometric mean of two internal controls. Data are mean fold change compared to control ± SEM. *P < 0.05; **P < 0.01. Data are representative of 3 independent experiments.
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f7: Effect of MitoTempo on inflammatory and redox signalling markers in HUVEC.HUVEC were pre-treated with 5 μM MitoTempo for 2 hrs prior to exposure to 100 ng/ml LPS for 24 hrs and gene expression of inflammatory markers were quantified by real-time PCR. (a) Gene expression of inflammatory markers TNF-α and endothelin-1 respectively was determined in LPS-stimulated HUVEC. Cells were pre-treated with 5 μM MitoTempo for 2 hrs prior to exposure to 200 μM H2O2 for 24hrs and gene expression of redox markers were quantified by real-time PCR. (b) Gene expression of redox signalling mediators, SOD1, SOD2, HO-1, UCP-1and TLR-9 respectively were determined in HUVEC following oxidative stress insult. The amounts of amplified products are expressed relative to geometric mean of two internal controls. Data are mean fold change compared to control ± SEM. *P < 0.05; **P < 0.01. Data are representative of 3 independent experiments.

Mentions: To specifically elucidate the protective effects of mitochondrial targeted antioxidant, MitoTempo in regulating pathogenic cellular pathways in endothelial cells, HUVEC were pre-treated with MitoTempo prior to exposure to stressors including H2O2 (oxidative stress) and LPS (inflammation). Firstly, we examined the expression of inflammatory markers in response to 24 hrs stimulation with LPS (100 ng/ml) with/without 2 hrs MitoTempo (5 μM) pre-treatment. There was a significant decrease in TNF-α gene expression (2.09 ± 0.18 fold vs 0.99 ± 0.15 fold, n = 3, P < 0.01) (Fig. 7a) in cells pretreated with MitoTempo compared to untreated cells.


Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia
Effect of MitoTempo on inflammatory and redox signalling markers in HUVEC.HUVEC were pre-treated with 5 μM MitoTempo for 2 hrs prior to exposure to 100 ng/ml LPS for 24 hrs and gene expression of inflammatory markers were quantified by real-time PCR. (a) Gene expression of inflammatory markers TNF-α and endothelin-1 respectively was determined in LPS-stimulated HUVEC. Cells were pre-treated with 5 μM MitoTempo for 2 hrs prior to exposure to 200 μM H2O2 for 24hrs and gene expression of redox markers were quantified by real-time PCR. (b) Gene expression of redox signalling mediators, SOD1, SOD2, HO-1, UCP-1and TLR-9 respectively were determined in HUVEC following oxidative stress insult. The amounts of amplified products are expressed relative to geometric mean of two internal controls. Data are mean fold change compared to control ± SEM. *P < 0.05; **P < 0.01. Data are representative of 3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f7: Effect of MitoTempo on inflammatory and redox signalling markers in HUVEC.HUVEC were pre-treated with 5 μM MitoTempo for 2 hrs prior to exposure to 100 ng/ml LPS for 24 hrs and gene expression of inflammatory markers were quantified by real-time PCR. (a) Gene expression of inflammatory markers TNF-α and endothelin-1 respectively was determined in LPS-stimulated HUVEC. Cells were pre-treated with 5 μM MitoTempo for 2 hrs prior to exposure to 200 μM H2O2 for 24hrs and gene expression of redox markers were quantified by real-time PCR. (b) Gene expression of redox signalling mediators, SOD1, SOD2, HO-1, UCP-1and TLR-9 respectively were determined in HUVEC following oxidative stress insult. The amounts of amplified products are expressed relative to geometric mean of two internal controls. Data are mean fold change compared to control ± SEM. *P < 0.05; **P < 0.01. Data are representative of 3 independent experiments.
Mentions: To specifically elucidate the protective effects of mitochondrial targeted antioxidant, MitoTempo in regulating pathogenic cellular pathways in endothelial cells, HUVEC were pre-treated with MitoTempo prior to exposure to stressors including H2O2 (oxidative stress) and LPS (inflammation). Firstly, we examined the expression of inflammatory markers in response to 24 hrs stimulation with LPS (100 ng/ml) with/without 2 hrs MitoTempo (5 μM) pre-treatment. There was a significant decrease in TNF-α gene expression (2.09 ± 0.18 fold vs 0.99 ± 0.15 fold, n = 3, P < 0.01) (Fig. 7a) in cells pretreated with MitoTempo compared to untreated cells.

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