Role of Mitochondrial Dysfunction and Reactive Oxygen Species in Mediating Hypertension in the Reduced Uterine Perfusion Pressure Rat Model of Preeclampsia

Abstract

Placental ischemia is believed to be the initial event in the development of preeclampsia. Mitochondrial dysfunction is a cause of reactive oxygen species (ROS) generation and oxidative stress, however, there are not many studies examining the role of mitochondrial ROS in the pathology of preeclampsia. The purpose of this study was to not only examine the effect of placental ischemia on mitochondrial-mediated oxidative stress in reduced uterine perfusion pressure (RUPP) rat model of preeclampsia but to also examine the role of mitochondrial ROS in contributing to hypertension in response to placental ischemia. Female pregnant Sprague Dawley rats were used in this study. On gestational day 14, RUPP surgery was performed. On gestational day 19, blood pressure (mean arterial pressure) was measured, placentas and kidneys were collected from normal pregnant and RUPP rats and processed for mitochondrial respiration, ROS, and oxidative phosphorylation enzyme activities. Renal and placental complex activities, expressions and respiration rates were significantly reduced and mitochondrial ROS was increased in RUPP versus normal pregnant mitochondria. Mean arterial pressure was elevated in RUPP (n=6) compared with normal pregnant rats (n=5; 126±4 versus 103±4 mm Hg; P<0.05) and treatment with mitochondrial-specific antioxidants (MitoQ/MitoTEMPO) significantly reduced mean arterial pressure in RUPPs (n=5-10). Mitochondrial ROS was significantly elevated in endothelial cells incubated with RUPP serum compared from with normal pregnant rats, whereas serum from mito antioxidant-treated RUPP rats attenuated this response. Impaired mitochondrial function and vascular, placental, and renal mitochondrial ROS play an important role in hypertension and reduced fetal weight in response to placental ischemia during pregnancy.

MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation

“…Damaged mitochondria induce cytotoxicity by producing superoxide radicals from the abnormal electron transport chain, and mitochondria are also vulnerable to ROS 35,36 . To detect whether the maintenance of mitochondrial quality was due to the inhibition of mtROS production, we used MitoTEMPO, a specific mtROS scavenger 37,38 , for treatment of liver I/R injury. Similar to previous finding reported by Sang et al, we found that Mito-TEMPO not only inhibited mtROS accumulation but also mitigated I/R-induced liver damage, as evidenced by a reduction in the level of serum hepatic enzymes and improvement in liver pathology 39 .…”

Schisandrin C targets Keap1 and attenuates oxidative stress by activating Nrf2 pathway in Ang II‐challenged vascular endothelium

“…Thus, endothelial dysfunction is considered an early independent predictor of CVDs. Extensive cellular and molecular studies have identified putative mediators, which include increased oxidative stress, inflammation, mitochondrial dysfunction, and endothelial cell (EC) apoptosis (Hou et al, ; Kroller‐Schon et al, ; Vaka et al, ), that participate in the progression of endothelial dysfunction. Among these various functional events, oxidative stress seems to be upstream of the cascade (Forstermann, Xia, & Li, ; McSweeney, Warabi, & Siow, ; Munzel et al, ).…”

A case‐comparison study of pregnant women with mitochondrial disease – what to expect?

“…Proteomic alterations relevant to the mitochondrial respiratory chain function and fatty acid oxidation have been reported previously in placentas from women with pre‐eclampsia, where morphological abnormalities of mitochondria were also noted . Recently, impaired mitochondrial function has been demonstrated to play an important role in the development of hypertension and reduced fetal weight in a rat model of pre‐eclampsia …”