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ALLAGNAT, F.

Publications and source records attributed to ALLAGNAT, F..

2 recordsLinked to original sources
bioRxiv2021

Hydrogen sulfide release via the ACE inhibitor Zofenopril prevents intimal hyperplasia in human vein segments and in a mouse model of carotid artery stenosis

ObjectivesHypertension is a major risk factor for intimal hyperplasia (IH) and restenosis following vascular and endovascular interventions. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, limits restenosis. While there is no clinically available pure H2S releasing compound, the sulfhydryl-containing angiotensin-converting enzyme inhibitor Zofenopril is a source of H2S. Here, we hypothesized that Zofenopril, due to H2S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitor (ACEi), in reducing intimal hyperplasia. MaterialsSpontaneously hypertensive male Cx40 deleted mice (Cx40-/-) or WT littermates were randomly treated with Enalapril 20 mg (Mepha Pharma) or Zofenopril 30 mg (Mylan SA). Discarded human vein segments and primary human smooth muscle cells (SMC) were treated with the active compound Enalaprilat or Zofenoprilat. MethodsIH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for 7 days ex vivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro. ResultsCompared to control animals (intima/media thickness=2.3{+/-}0.33), Enalapril reduced IH in Cx40-/- hypertensive mice by 30% (1.7{+/-}0.35; p=0.037), while Zofenopril abrogated IH (0.4{+/-}0.16; p<.0015 vs. Ctrl and p>0.99 vs. sham-operated Cx40-/- mice). In WT normotensive mice, enalapril had no effect (0.9665{+/-}0.2 in control vs 1.140{+/-}0.27; p>.99), while Zofenopril also abrogated IH (0.1623{+/-}0.07, p<.008 vs. Ctrl and p>0.99 vs. sham-operated WT mice). Zofenoprilat, but not Enalaprilat, also prevented intimal hyperplasia in human veins segments ex vivo. The effect of Zofenopril on carotid and SMC correlated with reduced SMC proliferation and migration. Zofenoprilat inhibited the MAPK and mTOR pathways in SMC and human vein segments. ConclusionZofenopril provides extra beneficial effects compared to non-sulfhydryl ACEi to reduce SMC proliferation and restenosis, even in normotensive animals. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases and hypertension. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/460108v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@a37b62org.highwire.dtl.DTLVardef@f977e0org.highwire.dtl.DTLVardef@2d3266org.highwire.dtl.DTLVardef@147d604_HPS_FORMAT_FIGEXP M_FIG C_FIG What this paper addsThe current strategies to reduce intimal hyperplasia (IH) principally rely on local drug delivery, in endovascular approach. The oral angiotensin converting enzyme inhibitor (ACEi) Zofenopril has additional effects compared to other non-sulfyhydrated ACEi to prevent intimal hyperplasia and restenosis. Given the number of patients treated with ACEi worldwide, these findings call for further prospective clinical trials to test the benefits of sulfhydrated ACEi over classic ACEi for the prevention of restenosis in hypertensive patients.

physiology↗
bioRxiv2021

Sodium Thiosulfate acts as an H2S mimetic to prevent intimal hyperplasia via inhibition of tubulin polymerization

BackgroundIntimal hyperplasia (IH) remains a major limitation in the long-term success of any type of revascularization. IH is due to vascular smooth muscle cell (VSMC) dedifferentiation, proliferation and migration. The gasotransmitter Hydrogen Sulfide (H2S) inhibits IH in pre-clinical models. However, there is currently no clinically approved H2S donor. Here we used sodium thiosulfate (STS), a clinically-approved source of sulfur, to limit IH. MethodsHypercholesterolemic LDLR deleted (LDLR-/-), WT or CSE-/- male mice randomly treated with 4g/L STS in the water bottle were submitted to focal carotid artery stenosis to induce IH. Human vein segments were maintained in culture for 7 days to induce IH. Further in vitro studies were conducted in primary human vascular smooth muscle cell (VSMC). FindingsSTS inhibited IH in mice and in human vein segments. STS inhibited cell proliferation in the carotid artery wall and in human vein segments. STS increased polysulfides in vivo and protein persulfidation in vitro, which correlated with microtubule depolymerization, cell cycle arrest and reduced VSMC migration and proliferation. InterpretationSTS, a drug used for the treatment of cyanide poisoning and calciphylaxis, protects against IH in a mouse model of arterial restenosis and in human vein segments. STS acts as an H2S donor to limit VSMC migration and proliferation via microtubule depolymerization. FundingThis work was supported by the Swiss National Science Foundation (grant FN-310030_176158 to FA and SD and PZ00P3-185927 to AL); the Novartis Foundation to FA; and the Union des Societes Suisses des Maladies Vasculaires to SD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/459573v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@c98479org.highwire.dtl.DTLVardef@1863f0org.highwire.dtl.DTLVardef@1492ad7org.highwire.dtl.DTLVardef@9bca8a_HPS_FORMAT_FIGEXP M_FIG C_FIG Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIntimal hyperplasia (IH) is a complex process leading to vessel restenosis, a major complication following cardiovascular surgeries and angioplasties. Therapies to limit IH are currently limited. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, limits restenosis. However, despite these potent cardiovascular benefits in pre-clinical studies, H2S-based therapeutics are not available yet. Sodium thiosulfate (Na2S2O3) is an FDA-approved drug used for the treatment of cyanide poisoning and calciphylaxis, a rare condition of vascular calcification affecting patients with end-stage renal disease. Evidence suggest that thiosulfate may generate H2S in vivo in pre-clinical studies. Added value of this studyHere, we demonstrate that STS inhibit IH in a surgical mouse model of IH and in an ex vivo model of IH in human vein culture. We further found that STS increases circulating polysulfide levels in vivo and inhibits IH via decreased cell proliferation via disruption of the normal cells cytoskeleton. Finally, using CSE knockout mice, the main enzyme responsible for H2S production in the vasculature, we found that STS rescue these mice from accelerated IF formation. Implications of all the available evidenceThese findings suggest that STS holds strong translational potentials to limit IH following vascular surgeries and should be investigated further.

physiology↗