Key result
ACE2 reduces acute lung injury-induced pulmonary cell apoptosis by inhibiting SMAD2 phosphorylation.
Why the study?
Although ACE2 suppresses acute lung injury (ALI) severity and has a possible role in suppressing ALI-induced apoptosis of pulmonary endothelial cells, the underlying mechanisms remained undetermined.
Does angiotensin-converting enzyme 2 (ACE2) inhibit pulmonary endothelial cell apoptosis during acute lung injury by suppressing SMAD2 phosphorylation?
Does angiotensin-converting enzyme 2 (ACE2) inhibit pulmonary endothelial cell apoptosis during acute lung injury by suppressing SMAD2 phosphorylation?
This preclinical study identifies a novel molecular pathway in which ACE2 suppresses acute lung injury-induced endothelial cell death by inhibiting SMAD2 phosphorylation.
Answers are grounded in this paper and cite their sources.
ACE2 may suppress ALI endothelial apoptosis via SMAD2; leaves open clinical translation pending human trials.
BACKGROUND/AIMS: Angiotensin converting enzyme 2 (ACE2) has an established role in suppressing the severity of acute lung injury (ALI), especially when it was applied together with transplantation of human umbilical cord mesenchymal stem cells (uMSCs). Although the effects of ACE2 in ALI are believed to mainly result from its role in hydrolyzing angiotensin II (AngII), which subsequently reduces the vascular tension and subsequent pulmonary accumulation of inflammatory cells, we and others have recently reported a possible role of ACE2 in suppressing the ALI-induced apoptosis of pulmonary endothelial cells. However, the underlying mechanisms remain undetermined. METHODS: Here, we analyzed the alteration in lung injury severity in ALI after ACE2, by histology and inflammatory cytokine levels. We analyzed apoptosis-associated proteins in lung after ALI, as well as in cultured endothelial cells treated with nitric oxide (NO). We overexpressed SMAD7 to inhibit SMAD2 signaling in cultured endothelial cells and examined its effects on NO-induced cell apoptosis. RESULTS: ACE2 alleviated severity of lung injury after ALI. ACE2 significantly decreased the ALI-induced apoptosis of pulmonary cells in vivo, and ACE2 protected endothelial cells against NO-induced apoptosis in vitro. NO induced phosphorylation of a key factor of transforming growth factor β (TGF β) receptor signaling, SMAD2, which could be dose-dependently inhibited by ACE2. Inhibition of SMAD2 phosphorylation through expression of its inhibitor SMAD7 significantly inhibited NO-induced cell apoptosis, without need for ACE2. CONCLUSION: Our data suggest that ACE2-mediated AngII degradation may inhibit AngII-mediated SMAD2-phophorylation, possibly through a TGFβ-independent manner, which subsequently suppresses the ALI-induced cell death. Our results thus reveal a novel molecular pathway that controls the pathogenesis of ALI.
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Ji et al. (2015) studied Acute lung injury (ALI). Angiotensin-converting enzyme 2 (ACE2) and SMAD7 overexpression was evaluated on Lung injury severity and pulmonary endothelial cell apoptosis. ACE2 significantly decreased acute lung injury-induced apoptosis of pulmonary cells in vivo and dose-dependently inhibited nitric oxide-induced SMAD2 phosphorylation and apoptosis in vitro.
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