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 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 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@ded9a9org.highwire.dtl.DTLVardef@a4036aorg.highwire.dtl.DTLVardef@1dc3c12org.highwire.dtl.DTLVardef@1ebcae7_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.