Key result
Zofenopril reduces intimal hyperplasia ~83% vs control in hypertensive mice and human veins ex vivo.
Why the study?
Hypertension promotes intimal hyperplasia and re-stenosis, and it was hypothesized that the sulfhydryl-containing ACE inhibitor zofenopril would reduce intimal hyperplasia superior to non-sulfhydryl ACE inhibitors via hydrogen sulphide release.
Does zofenopril reduce intimal hyperplasia compared to enalapril in mouse models of carotid artery stenosis and human vein segments?
Does zofenopril reduce intimal hyperplasia compared to enalapril in mouse models of carotid artery stenosis and human vein segments?
Absolute Event Rate: 0.4% vs 2.3%
p-value: p=<0.002
Zofenopril, a sulfhydryl-containing ACE inhibitor, prevents intimal hyperplasia more effectively than non-sulfhydryl ACE inhibitors in both hypertensive and normotensive models, likely via hydrogen sulphide release.
Zofenopril may reduce restenosis beyond standard ACE inhibition; leaves open prospective trials before clinical adoption.
Objective Hypertension is a major risk factor for intimal hyperplasia (IH) and re-stenosis following vascular and endovascular interventions. Preclinical studies suggest that hydrogen sulphide (H 2 S), an endogenous gasotransmitter, limits re-stenosis. While there is no clinically available pure H 2 S releasing compound, the sulfhydryl containing angiotensin converting enzyme inhibitor zofenopril is a source of H 2 S. Here, it was hypothesised that zofenopril, due to H 2 S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitors (ACEi) in reducing intimal hyperplasia. Methods Spontaneously hypertensive male Cx40 deleted mice (Cx40 –/– ) or wild type (WT) littermates were randomly treated with enalapril 20 mg or zofenopril 30 mg. Discarded human vein segments and primary human smooth muscle cells (SMCs) were treated with the active compound enalaprilat or zofenoprilat. IH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for seven days ex vivo . Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro. Results Compared with control animals (intima/media thickness 2.3 ± 0.33 μm), enalapril reduced IH in Cx40 –/– hypertensive mice by 30% (1.7 ± 0.35 μm; p = .037), while zofenopril abrogated IH (0.4 ± 0.16 μm; p < .002 vs. control and p > .99 vs. sham operated Cx40 –/– mice). In WT normotensive mice, enalapril had no effect (0.9665 ± 0.2 μm in control vs. 1.140 ± 0.27 μm; p > .99), while zofenopril also abrogated IH (0.1623 ± 0.07 μm; p < .008 vs. control and p > .99 vs. sham operated WT mice). Zofenoprilat, but not enalaprilat, also prevented IH in human vein segments ex vivo . The effect of zofenopril on carotid and SMCs correlated with reduced SMC proliferation and migration. Zofenoprilat inhibited the mitogen activated protein kinase and mammalian target of rapamycin pathways in SMCs and human vein segments. Conclusion Zofenopril provides extra beneficial effects compared with non-sulfhydryl ACEi in reducing SMC proliferation and re-stenosis, even in normotensive animals. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases and hypertension.
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Macabrey et al. (2021) studied Intimal hyperplasia and re-stenosis. Zofenopril / Zofenoprilat vs. Enalapril (20 mg) / Enalaprilat or Control was evaluated on Intimal hyperplasia (intima/media thickness) (p=<0.002). Zofenopril abrogated intimal hyperplasia in hypertensive mice compared to control (0.4 ± 0.16 μm vs 2.3 ± 0.33 μm; p<0.002) and prevented it in human vein segments ex vivo.
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