Fig. 2
From: Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents
Molecular mechanisms of doxorubicin induced endothelial damage and reversion by the SH-containing ACEi zofenoprilat. Exposure of bovine coronary post-capillary venular endothelial cells to doxorubicin (D) impaired cell survival by promoting their apoptosis (evaluated as cleaved caspase-3: Cl. Caspase 3). ERK1/2 related p53 activation was responsible for doxorubicin induced caspase-3 cleavage. pERK1/2 and p53 were evaluated by western blot in EC treated with 0.5 μM doxorubicin (D) for 1 h, while the cleavage of caspase-3 was monitored by western blotting in EC exposed to doxorubicin for 6 h. P53 mediated-apoptosis and impairment of survival were reverted by treatment with zofenoprilat (Z), added at 1–100 μM concentration together with doxorubicin. The previously described prosurvival signaling pathway (activation of PI-3K dependent eNOS and upregulation of endogenous FGF-2 and telomease reverse transcriptase TERT) [77] was not involved in the protective effect of doxorubicin induced damage, which, instead, could be ascribed to cystathionine gamma lyase (CSE) dependent availability of H2S from zofenoprilat. Indeed the levels of CSE protein were upregulated by zofenoprilat treatment (10 μM, 4 h) [78]