Sanchez-Aranguren Lissette Carolina, Rezai Homira, Ahmad Shakil, Alzahrani Faisal A, Sparatore Anna, Wang Keqing, Ahmed Asif
Aston Medical Research Institute, Aston Medical School, Birmingham B4 7ET, UK.
Mirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Holt Street, Birmingham B7 4BB, UK.
Antioxidants (Basel). 2020 Jul 9;9(7):598. doi: 10.3390/antiox9070598.
Hypertensive disorder in pregnancy is a major cause of maternal and perinatal mortality worldwide. Women who have had preeclampsia are at three to four times higher risk in later life of developing high blood pressure and heart disease. Soluble Flt-1 (sFlt-1) is elevated in preeclampsia and may remain high postpartum in women with a history of preeclampsia. Heme oxygenase-1 (Hmox1/HO-1) exerts protective effects against oxidative stimuli and is compromised in the placenta of pregnant women with preeclampsia. We hypothesized that sFlt-1 inhibits cardiac mitochondrial activity in HO-1 deficient mice. HO-1 haplo-insufficient mice (Hmox1) were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) or control virus (Ad-CMV). Subsequently, they were treated daily with either placebo or MZe786 for six days, when the heart tissue was harvested to assess cardiac mitochondrial activity. Here, we show that the loss of HO-1 disturbed cardiac mitochondrial respiration and reduced mitochondrial biogenesis. The overexpression of sFlt-1 resulted in the inhibition of the cardiac mitochondrial activity in Hmox1 mice. The present study demonstrates that the hydrogen sulfide (HS) releasing molecule, MZe786, rescues mitochondrial activity by stimulating cardiac mitochondrial biogenesis and antioxidant defense in Hmox1 mice and in Hmox1 mice exposed to a high sFlt-1 environment.
妊娠期高血压疾病是全球孕产妇和围产期死亡的主要原因。患有先兆子痫的女性在晚年患高血压和心脏病的风险要高出三到四倍。可溶性Flt-1（sFlt-1）在先兆子痫中升高，并且在有先兆子痫病史的女性产后可能仍然居高不下。血红素加氧酶-1（Hmox1/HO-1）对氧化刺激具有保护作用，并且在患有先兆子痫的孕妇胎盘中受损。我们假设sFlt-1会抑制HO-1缺陷小鼠的心脏线粒体活性。给HO-1单倍体不足小鼠（Hmox1）注射编码sFlt-1的腺病毒（Ad-sFlt-1）或对照病毒（Ad-CMV）。随后，它们每天接受安慰剂或MZe786治疗六天，之后采集心脏组织以评估心脏线粒体活性。在此，我们表明HO-1的缺失扰乱了心脏线粒体呼吸并减少了线粒体生物合成。sFlt-1的过表达导致Hmox1小鼠心脏线粒体活性受到抑制。本研究表明，释放硫化氢（HS）的分子MZe786通过刺激Hmox1小鼠以及暴露于高sFlt-1环境的Hmox1小鼠的心脏线粒体生物合成和抗氧化防御来挽救线粒体活性。
