MZe786 Rescues Cardiac Mitochondrial Activity in High sFlt-1 and Low HO-1 Environment

Abstract

<jats:p>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 (H2S) 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.</jats:p>

Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model

“…MZe786 suppressed the increase sFlt-1 that was a likely result of decreased CSE expression in the mRUPP model. As observed in our earlier publications [ 19 ], this was probably due, in part, to the increased expression of the antioxidant genes and improved mitochondrial biogenesis that suppressed oxidative stress.…”

“…We recently reported that MZe786 rescues mitochondrial activity by stimulating cardiac mitochondrial biogenesis and antioxidant defence in heme oxygenase-1 deficient mice under high sFlt-1 environment [ 19 ]. With a good safety profile, MZe786 was a good H 2 S releasing candidate for testing in an animal model of preeclampsia [ 20 ].…”

“…Surgically induced preeclampsia consistently showed increased maternal and fetal expression levels of sFlt-1 and marked reduction in the placental expression of CSE. Our recent studies have shown that CSE/H 2 S pathway sustain endothelial mitochondrial bioenergetics and loss of CSE increased the production of mitochondrial-specific superoxide [ 19 ]. Mitochondria are the main source of reactive oxygen species during ischemia in renal tissue [ 57 ].…”

“…PGC-1α is also a master regulator of mitochondrial biogenesis signals [ 60 ]. We recently demonstrated the ability of MZe786 to rescue mitochondrial biogenesis and anti-oxidant defence in heme oxygenase-1 deficient mice exposed to a high sFlt-1 environment [ 19 ]. Here, we show that MZe786 successfully reduced maternal and fetal sFlt-1 levels and reduced oxidative stress in mRUPP kidneys as evidenced by decreased nitrotyrosine staining.…”

“…The H 2 S-releasing molecule, MZe786 (2-acetyloxybenzoic acid 4-(3-thioxo-3 H -1,2-dithiol-5-yl)phenyl ester) with a defined pharmacological profile, was used as previously described [ [19] , [20] , [21] ].…”