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

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.

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

“…In conclusion, the development of this refined surgically induced model of preeclampsia that captures major preeclampsia features including up-regulation of sFlt-1 and down-regulation of protective enzymes offers a unique opportunity to test novel therapeutics for the prevention of preeclampsia. MZe786 significantly limited the development of preeclampsia in the mRUPP model by suppressing sFlt-1 and nitrosative stress as well as improving antioxidant genes [ 21 ] and cellular mitochondrial function [ 64 , 65 ]. This compound warrants urgent investigation in clinical settings.…”

Sodium Thiosulphate-Loaded Liposomes Control Hydrogen Sulphide Release and Retain Its Biological Properties in Hypoxia-like Environment

“…Recently, the use of H 2 S donors has been recognised as a potential approach to modulate cellular bioenergetics and ATP production in a myriad of adverse pathological conditions [ 37 , 42 , 43 , 44 , 45 , 46 ]. Furthermore, as others have previously reported, under hypoxia, cells fail to activate mitochondrial respiration, relying primarily on glycolysis for energy supply [ 47 , 48 ].…”

“…Following, to evaluate mitochondrial and glycolytic function, a set of drugs/inhibitors: oligomycin (O) (1 mM) (Sigma-Aldrich, Dorset, UK), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) (0.5 mM) (Sigma-Aldrich, Dorset, UK), 2 deoxy glucose (2-DG) (Sigma-Aldrich, Dorset, UK) and a mixture of rotenone and antimycin A (Rot/AntA) (1 mM) (Cayman Chemicals, Michigan, USA) were injected sequentially, using available ports to: inhibit the ATP synthase, uncouple oxidative phosphorylation, inhibit glycolysis and estimate non-mitochondrial respiration, respectively. From OCR readings, this experiment measures six parameters of the mitochondrial function: basal oxygen consumption, ATP-linked oxygen consumption, proton leak, maximal oxygen consumption, reserve capacity, and non-mitochondrial oxygen consumption as we have previously optimised [ 37 , 38 , 39 ] ( Supplementary Figure S1A ). From ECAR readings, the experiment allowed to calculate three glycolysis related parameters: basal glycolysis, glycolytic capacity and glycolytic dependence ( Supplementary Figure S1B ).…”

The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases

“…Besides, a recent study demonstrated that suppression of CSE in human umbilical vein endothelial cells (HUVECs) results in mitochondria dysfunction by elevating the expression of soluble anti-angiogenic markers, fms-like tyrosine kinase-1 and endoglins, whereas supplementation of H 2 S by the donor AP39 could reverse the effect and improve cellular bioenergetics and reactive oxygen species (ROS) levels [ 72 ]. The treatment of HUVECs with a hybrid H 2 S and NO donor, ZYZ-803, has also been demonstrated to promote angiogenic properties by activating the signal of transducer and activator of transcription 3 (STAT-3)/Ca 2+ /calmodulin-dependent protein kinase II signaling cascade [ 73 ].…”