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

Lissette Carolina Sanchez-Aranguren,Faisal A Alzahrani,Shakil Ahmad,Anna Sparatore,Homira Rezai,Keqing Wang,Asif Ahmed

doi:10.3390/antiox9070598

Lissette Carolina Sanchez-Aranguren, Faisal A Alzahrani + Show 5 more

Open Access

https://doi.org/10.3390/antiox9070598

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Abstract

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.

Highlights

Preeclampsia is a pregnancy-related complication that affects more than 10 million women a year and is the leading cause of maternal and perinatal morbidity and mortality worldwide [1,2,3]
We have previously demonstrated using serum obtained from women with preeclampsia that increased levels of Soluble Flt-1 (sFlt-1) leads to metabolic perturbations accountable for mitochondrial dysfunction in cultured endothelial cells
Our results indicate that sFlt-1 is damaging to the mitochondria of cardiac tissue and imply that sFlt-1-induced cardiac mitochondrial dysfunction is a potential molecular mechanism of cardiovascular disease in women, post preeclampsia

Summary

Introduction

Preeclampsia is a pregnancy-related complication that affects more than 10 million women a year and is the leading cause of maternal and perinatal morbidity and mortality worldwide [1,2,3]. It is recognized as an independent risk factor for heart diseases. Women who have had preeclampsia are three to four times more at risk of developing high blood pressure and are twice as likely to develop heart disease, heart failure, and stroke later in life [9,10,11]. The risk of cardiovascular complications further increases in women with a history of preeclampsia and preterm delivery, low birthweight babies or those who have suffered from severe preeclampsia [10,12,13].

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