MZe786, a hydrogen sulfide-releasing aspirin prevents preeclampsia in heme oxygenase-1 haplodeficient pregnancy under high soluble flt-1 environment

Homira Rezai,Shakil Ahmad,Faisal A Alzahrani,Lissette Sanchez-Aranguren,Irundika Hk Dias,Swati Agrawal,Anna Sparatore,Keqing Wang,Asif Ahmed

doi:10.1016/j.redox.2020.101768

Abstract

Preeclampsia affects one in twelve of the 130 million pregnancies a year. The lack of an effective therapeutic to prevent or treat it is responsible for an annual global cost burden of 100 billion US dollars. Preeclampsia also affects these women later in life as it is a recognised risk factor for cardiovascular disease, stroke and vascular dementia. Our laboratory demonstrated that preeclampsia is associated with high soluble fms-like tyrosine kinase 1 (sFlt-1) and low heme oxygenase-1 (HO1/Hmox1) expression. Here we sought to determine the therapeutic value of a novel H2S-releasing aspirin (MZe786) in HO-1 haploid deficient (Hmox1+/−) pregnant mice in a high sFlt-1 environment. Pregnant Hmox1+/− mice were injected with adenovirus encoding sFlt-1 or control virus at gestation day E11.5. Subsequently, Hmox1+/− dams were treated daily with a number of treatment regimens until E17.5, when maternal and fetal outcomes were assessed. Here we show that HO-1 compromised mice in a high sFlt-1 environment during pregnancy exhibit severe preeclampsia signs and a reduction in antioxidant genes. MZe786 ameliorates preeclampsia by reducing hypertension and renal damage possibly by stimulating antioxidant genes. MZe786 also improved fetal outcome in comparison with aspirin alone and appears to be a better therapeutic agent at preventing preeclampsia than aspirin alone.

Highlights

Preeclampsia is a systemic disorder of pregnancy, affecting over 10 million women and annually accounts for over 76,000 maternal deaths and 500,000 infant deaths [1,2,3]
Earlier studies demonstrated that HO-1 is a negative regulator of soluble fms-like tyrosine kinase 1 (sFlt-1) [19] and is decreased in preeclampsia [18]
Overexpression of sFlt-1 leads to high blood pressure, kidney damage and fetal growth restriction as previously reported in pregnant rat [46] and mice [47]

Summary

Introduction

Preeclampsia is a systemic disorder of pregnancy, affecting over 10 million women and annually accounts for over 76,000 maternal deaths and 500,000 infant deaths [1,2,3]. This equates to a life lost every minute. Rodents treated with adenovirus encoding sFlt-1 develop preeclampsia-like phenotype with high blood pressure and kidney damage [12, 14]. First trimester chorionic villous (fetal placental cells) sampling revealed a reduction in Hmox mRNA from women who subsequently went on to develop preeclampsia compared to normal pregnancy [21]. A more recent study showed that that guanine-thymine (GTn) microsatellite in the Hmox promoter decreases HO-1 expression and there was an association between long fetal and maternal GTn repeats and lower placental and serum

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Conclusion