BACKGROUND AND PURPOSE: Hydrogen sulfide (H2 S), an endogenous volatile mediator with pleiotropic functions, promotes vasorelaxation, exerts anti-inflammatory actions and regulates angiogenesis. Previously, the SH-containing angiotensin-converting enzyme inhibitor (ACEI), zofenopril, was identified as being effective in preserving endothelial function and inducing angiogenesis among ACEIs. Based on the H2 S donor property of its active metabolite zofenoprilat, the objective of this study was to evaluate whether zofenoprilat-induced angiogenesis was due to increased H2 S availability. EXPERIMENTAL APPROACH: HUVECs were used for in vitro studies of angiogenesis, whereas the Matrigel plug assay was used for in vivo assessments. KEY RESULTS: Zofenoprilat-treated HUVECs showed an increase in all functional features of the angiogenic process in vitro. As zofenoprilat induced the expression of CSE (cystathionine-γ-lyase) and the continuous production of H2 S, CSE inhibition or silencing blocked the ability of zofenoprilat to induce angiogenesis, both in vitro and in vivo. The molecular mechanisms underlying H2 S/zofenoprilat-induced angiogenesis were dependent on Akt, eNOS and ERK1/2 cascades. ATP-sensitive potassium (KATP ) channels, the molecular target that mediates part of the vascular functions of H2 S, were shown to be involved in the upstream activation of Akt and ERK1/2. Moreover, the up-regulation of fibroblast growth factor-2 was dependent on CSE-derived H2 S response to H2 S and KATP activation. CONCLUSIONS AND IMPLICATIONS: Zofenoprilat induced a constant production of H2 S that stimulated the angiogenic process through a KATP channel/Akt/eNOS/ERK1/2 pathway. Thus, zofenopril can be considered as a pro-angiogenic drug acting through H2 S release and production, useful in cardiovascular pathologies where vascular functions need to be re-established and functional angiogenesis induced.

Terzuoli, E., Monti, M., Vellecco, V., Bucci, M., Cirino, G., Ziche, M., et al. (2015). Characterization of zofenoprilat as an inducer of functional angiogenesis through increased H2 S availability. BRITISH JOURNAL OF PHARMACOLOGY, 172(12), 2961-2973 [10.1111/bph.13101].

Characterization of zofenoprilat as an inducer of functional angiogenesis through increased H2 S availability

TERZUOLI, ERIKA;MONTI, MARTINA;ZICHE, MARINA;MORBIDELLI, LUCIA
2015-01-01

Abstract

BACKGROUND AND PURPOSE: Hydrogen sulfide (H2 S), an endogenous volatile mediator with pleiotropic functions, promotes vasorelaxation, exerts anti-inflammatory actions and regulates angiogenesis. Previously, the SH-containing angiotensin-converting enzyme inhibitor (ACEI), zofenopril, was identified as being effective in preserving endothelial function and inducing angiogenesis among ACEIs. Based on the H2 S donor property of its active metabolite zofenoprilat, the objective of this study was to evaluate whether zofenoprilat-induced angiogenesis was due to increased H2 S availability. EXPERIMENTAL APPROACH: HUVECs were used for in vitro studies of angiogenesis, whereas the Matrigel plug assay was used for in vivo assessments. KEY RESULTS: Zofenoprilat-treated HUVECs showed an increase in all functional features of the angiogenic process in vitro. As zofenoprilat induced the expression of CSE (cystathionine-γ-lyase) and the continuous production of H2 S, CSE inhibition or silencing blocked the ability of zofenoprilat to induce angiogenesis, both in vitro and in vivo. The molecular mechanisms underlying H2 S/zofenoprilat-induced angiogenesis were dependent on Akt, eNOS and ERK1/2 cascades. ATP-sensitive potassium (KATP ) channels, the molecular target that mediates part of the vascular functions of H2 S, were shown to be involved in the upstream activation of Akt and ERK1/2. Moreover, the up-regulation of fibroblast growth factor-2 was dependent on CSE-derived H2 S response to H2 S and KATP activation. CONCLUSIONS AND IMPLICATIONS: Zofenoprilat induced a constant production of H2 S that stimulated the angiogenic process through a KATP channel/Akt/eNOS/ERK1/2 pathway. Thus, zofenopril can be considered as a pro-angiogenic drug acting through H2 S release and production, useful in cardiovascular pathologies where vascular functions need to be re-established and functional angiogenesis induced.
2015
Terzuoli, E., Monti, M., Vellecco, V., Bucci, M., Cirino, G., Ziche, M., et al. (2015). Characterization of zofenoprilat as an inducer of functional angiogenesis through increased H2 S availability. BRITISH JOURNAL OF PHARMACOLOGY, 172(12), 2961-2973 [10.1111/bph.13101].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/976996