Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia.
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.
The Irish Centre for Fetal and Neonatal Translational Research (INFANT), Department of Obstetrics and Gynaecology, Cork University Hospital, Wilton, Cork, Ireland.
Cathal
C
McCarthy
The Irish Centre for Fetal and Neonatal Translational Research (INFANT), Department of Obstetrics and Gynaecology, Cork University Hospital, Wilton, Cork, Ireland.
Louise C
LC
Kenny
D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007249:Inflammation / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D011225:Pre-Eclampsia / Q000097:blood / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D011247:Pregnancy; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D015415:Biomarkers; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013481:Superoxides; D006861:Hydrogen Peroxide