TY - JOUR
T1 - AP39, a Modulator of Mitochondrial Bioenergetics, Reduces Antiangiogenic Response and Oxidative Stress in Hypoxia-Exposed Trophoblasts
T2 - Relevance for Preeclampsia Pathogenesis
AU - Covarrubias, Ambart E.
AU - Lecarpentier, Edouard
AU - Lo, Agnes
AU - Salahuddin, Saira
AU - Gray, Kathryn J.
AU - Karumanchi, S. Ananth
AU - Zsengellér, Zsuzsanna K.
N1 - Publisher Copyright:
© 2019 American Society for Investigative Pathology
PY - 2019/1
Y1 - 2019/1
N2 - Although the cause of preeclampsia, a pregnancy complication with significant maternal and neonatal morbidity, has not been fully characterized, placental ischemia attributable to impaired spiral artery remodeling and abnormal secretion of antiangiogenic factors are thought to be important in the pathogenesis of the disease. Placental ischemia could impair trophoblast mitochondrial function and energy production, leading to the release of reactive oxygen species (ROS). ROS have been shown to stabilize hypoxia-inducible factor (HIF)-1α which, in turn, may induce transcription of antiangiogenic factors, soluble fms-like tyrosine kinase 1 (sFLT1), and soluble endoglin in trophoblasts. Herein, we tested whether the angiogenic imbalance and oxidative stress in the preeclamptic placenta may be prevented by improving mitochondrial function. First, to evaluate the cause–effect relationship between mitochondrial function and sFLT1 production, a human trophoblast primary cell culture model was established in which hypoxia induced mitochondrial ROS production and concurrent sFLT1 increase. Second, treatment with AP39, a novel mitochondria-targeted hydrogen sulfide donor, prevented ROS production, reduced HIF-1α protein levels, and diminished sFLT1 production. Finally, AP39, a modulator of mitochondrial bioenergetics enhanced cytochrome c oxidase activity, reversed oxidative stress and antiangiogenic response in hypoxic trophoblasts. These results suggest that placental hypoxia induces ROS production, HIF-1α stabilization, and sFLT1 up-regulation; these pathophysiological alterations can be attenuated by mitochondrial-targeted antioxidants.
AB - Although the cause of preeclampsia, a pregnancy complication with significant maternal and neonatal morbidity, has not been fully characterized, placental ischemia attributable to impaired spiral artery remodeling and abnormal secretion of antiangiogenic factors are thought to be important in the pathogenesis of the disease. Placental ischemia could impair trophoblast mitochondrial function and energy production, leading to the release of reactive oxygen species (ROS). ROS have been shown to stabilize hypoxia-inducible factor (HIF)-1α which, in turn, may induce transcription of antiangiogenic factors, soluble fms-like tyrosine kinase 1 (sFLT1), and soluble endoglin in trophoblasts. Herein, we tested whether the angiogenic imbalance and oxidative stress in the preeclamptic placenta may be prevented by improving mitochondrial function. First, to evaluate the cause–effect relationship between mitochondrial function and sFLT1 production, a human trophoblast primary cell culture model was established in which hypoxia induced mitochondrial ROS production and concurrent sFLT1 increase. Second, treatment with AP39, a novel mitochondria-targeted hydrogen sulfide donor, prevented ROS production, reduced HIF-1α protein levels, and diminished sFLT1 production. Finally, AP39, a modulator of mitochondrial bioenergetics enhanced cytochrome c oxidase activity, reversed oxidative stress and antiangiogenic response in hypoxic trophoblasts. These results suggest that placental hypoxia induces ROS production, HIF-1α stabilization, and sFLT1 up-regulation; these pathophysiological alterations can be attenuated by mitochondrial-targeted antioxidants.
UR - http://www.scopus.com/inward/record.url?scp=85058010832&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2018.09.007
DO - 10.1016/j.ajpath.2018.09.007
M3 - Article
C2 - 30315766
AN - SCOPUS:85058010832
SN - 0002-9440
VL - 189
SP - 104
EP - 114
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -