Bioenergetic effects of hydrogen sulfide suppress soluble Flt-1 and soluble endoglin in cystathionine gamma-lyase compromised endothelial cells

Lissette Carolina Sanchez-Aranguren,Homira Rezai,Faisal A Alzahrani,Shakil Ahmad,Asif Ahmed,Keqing Wang,Irundika H K Dias

doi:10.1038/s41598-020-72371-2

Lissette Carolina Sanchez-Aranguren, Homira Rezai + Show 5 more

Open Access

https://doi.org/10.1038/s41598-020-72371-2

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Abstract

Endothelial dysfunction is a hallmark of preeclampsia, a life-threatening complication of pregnancy characterised by hypertension and elevated soluble Fms-Like Tyrosine Kinase-1 (sFlt-1). Dysregulation of hydrogen sulfide (H2S) by inhibition of cystathionine γ-lyase (CSE) increases sFlt-1 and soluble endoglin (sEng) release. We explored whether compromise in CSE/H2S pathway is linked to dysregulation of the mitochondrial bioenergetics and oxidative status. We investigated whether these effects were linked to CSE-induced sFlt-1 and sEng production in endothelial cells. Here, we demonstrate that CSE/H2S pathway sustain endothelial mitochondrial bioenergetics and loss of CSE increases the production of mitochondrial-specific superoxide. As a compensatory effect, low CSE environment enhances the reliance on glycolysis. The mitochondrial-targeted H2S donor, AP39, suppressed the antiangiogenic response and restored the mitochondrial bioenergetics in endothelial cells. AP39 revealed that upregulation of sFlt-1, but not sEng, is independent of the mitochondrial H2S metabolising enzyme, SQR. These data provide new insights into the molecular mechanisms for antiangiogenic upregulation in a mitochondrial-driven environment. Targeting H2S to the mitochondria may be of therapeutic benefit in the prevention of endothelial dysfunction associated with preeclampsia.

Highlights

Oxidative stress and elevated antiangiogenic growth factors[1,2,3] are recognised markers of preeclampsia
We sought to explore whether a compromise in the CSE/H2S pathway is linked to dysregulation of the mitochondrial bioenergetics and oxidative stress and to investigate if these effects are linked to soluble Fms-Like Tyrosine Kinase-1 (sFlt-1) and soluble endoglin (sEng) production in CSE compromised human umbilical vein endothelial cells (HUVEC)
To study whether endogenous CSE-dependant H2S has a role in the regulation of endothelial cells bioenergetics, we inhibited CSE mRNA levels by small-interfering RNA (siRNA) transfection in HUVEC and evaluated the mitochondrial function and cellular oxidative status

Summary

Introduction

Oxidative stress and elevated antiangiogenic growth factors[1,2,3] are recognised markers of preeclampsia. Others have shown that chronic infusion of recombinant sFlt-1 on a daily basis for eight days to pregnant rats led to increased vascular superoxide production[24] and exacerbated oxidative stress, provoked mitochondrial swelling and induced apoptosis in trophoblasts in sFlt-1-injected m ice[25] These observations suggest that high circulating sFlt-1 contributes to vascular dysfunction by modulating the mitochondrial integrity in endothelial cells and placenta. AP39 revealed that upregulation of sFlt-1, but not sEng is independent of the mitochondrial H2S metabolising enzyme, sulfide quinone oxidoreductase (SQR) These results suggest that therapeutically targeting H 2S to the mitochondria should be considered in the management of endothelial dysfunction associated with preeclampsia

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