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THE ROLE OF MITOCHONDRIAL OXIDATIVE STRESS IN THE PATHOPHYSIOLOGY OF PREECLAMPSIA
Author(s) -
Vaka Venkat Ramana,
McMaster Kristen,
Ibrahim Tarek,
Cornelius Denise,
Amaral Lorena,
Wallace Kedra,
LaMarca Babbette
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.729.7
Subject(s) - mitochondrion , oxidative stress , mitochondrial ros , oxidative phosphorylation , reactive oxygen species , andrology , respiration , biology , medicine , chemistry , endocrinology , microbiology and biotechnology , biochemistry , anatomy
Preeclampsia (PE), is characterized by new onset hypertension and is associated with placental ischemia and oxidative stress. Placental ischemia is believed to be the initial event in the development of PE. Mitochondria are the major source of oxidative stress, the mitochondrial (mt) dysfunction leads to decreased respiration and increased mitochondrial reactive oxygen species (mtROS). The goal of our study is to determine if mt dysfunction and mtROS play a role in the pathology of PE. We hypothesize that PE placenta exhibit greater mt dysfunction and mtROS locally and peripherally which contribute to decreased mt respiration and in turn the development of hypertension during pregnancy. Methods Normal pregnant (NP) and PE patients were consented to collect placentas after delivery at the University of Mississippi Medical Center. Placentas were collected immediately after delivery and mitochondria were isolated using differential centrifugation. Mt function was assessed by studying respiration using complex I and II substrates, glutamate/malate and succinate respectively. Respiration measurements included: basal state (isolated mitochondria with no substrates), state 2 (glutamate and malate as complex I substrates), state 3 (ADP stimulated), leak state (oligomycin induced ATP synthase inhibition), and maximal state (FCCP stimulated uncoupled) were obtained using Oxygraph‐2k. MtROS production in human umbilical vein endothelial cells (HUVEC) was determined by bioassays using mitosox, a mitochondrial targeted dye, and flow cytometry. Mitochondrial targeted antioxidant, mitoQ was added to confirm the role of mitochondria in the production of ROS. Data are expressed as mean±SEM, statistical analysis included student t test or one way ANOVA and Bonferroni post hoc test. Results Placental complex I mediated state 3 (177±52 vs. 299±81 pmol/sec/mg,) and uncoupled (290±60 vs. 509±171 pmol/sec/mg) respiration rates; placental complex II mediated state 3 (229±53 vs. 404±44) and uncoupled (270±58 vs. 533±127, p<0.05) respiration rates were reduced in PE (n=6) vs. NP (n=6) mitochondria. HUVECs incubated with PE serum (n=8) show increased mtROS vs. NP serum (n=8) (92±1 vs 83±3, p<0.05) and was significantly reduced with mitoQ (n=6, 79±2, p<0.05 vs. PE). Conclusion The reduction in placental mt respiration indicate mitochondrial dysfunction in PE patients. Increased mtROS in HUVECs indicate the importance of circulating factors to stimulate mtROS in the vascular cells. Reduction in mtROS in HUVECs incubated with mitoQ indicate that targeting mitochondrial oxidative stress could be a therapeutic strategy to improve vascular function and could be a potential benefit to treating PE. Support or Funding Information RO1HD067541(BL)/Office of Research, UMMC. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .