Angiotensin-(1-7)/Mas Signaling Inhibits Lipopolysaccharide-Induced ADAM17 Shedding Activity and Apoptosis in Alveolar Epithelial Cells

Abstract

A disintegrin and metalloproteinase (ADAM) 17, constitutively expressed in alveolar epithelium, is the pivotal shedding enzyme mediating acute lung inflammation. On the other hand, angiotensin (Ang)-(1-7)/Mas signaling has been shown to improve acute respiratory distress syndrome and protect alveolar epithelial cells from apoptosis. In this study, we explored the effect of Ang-(1-7)/Mas signaling on the expression and activity of ADAM17 and assessed its impact on apoptosis in lipopolysaccharide (LPS)-treated human alveolar epithelial cells. LPS markedly induced the shedding activity of ADAM17 in alveolar epithelial cells, which was blocked by selective c-Jun N-terminal kinase (JNK) inhibitor SP600125. Ang-(1-7) concentration-dependently inhibited LPS-induced ADAM17 shedding activity, which was abolished by selective Mas blocker A779 and Mas shRNA. LPS and Ang-(1-7) showed no significant effect on the expression of ADAM17. Overexpression of ADAM17 synergized with LPS on increasing the shedding activity of ADAM17 and apoptosis in alveolar epithelial cells, counteracting the inhibitory effects of Ang-(1-7). In addition, LPS significantly increased the JNK activity in alveolar epithelial cells; Ang-(1-7) concentration-dependently inhibited LPS-induced JNK activity, which was abolished by A779 and Mas shRNA. In conclusion, this study suggests that Ang-(1-7)/Mas signaling inhibits LPS-induced alveolar epithelial cell apoptosis by inhibiting LPS-induced shedding activity of ADAM17, likely by a JNK-dependent mechanism.

Bisphenol-A and Nonylphenol Induce Apoptosis in Reproductive Tract Cancer Cell Lines by the Activation of ADAM17

“…Since both compounds activate the shedding of ADAM17 substrates, we suggest that it is possible that two of the common activated phosphoproteins—c-Jun and Stat5a/b—could explain these effects. In fact, it has been observed that the modulation of c-Jun or Stat5a activation also modulates TNF shedding elicited by BPA and NP in cancer cell lines [72,73,74]. However, it remains to be investigated whether the activation of the phosphoproteins observed in the present study is due to a direct activation of BPA and NP or whether this activation is achieved indirectly, by the shedding and auto/paracrine activation of cognate receptors, which seems to be the case of BPA [69].…”

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

“…Although little is known concerning the physiological roles of the ACE2/ANG-(1-7)/MAS axis in the lung, it appears to be critically involved in pathophysiological processes in this organ. ANG-(1-7) has been reported to reduce lung inflammation, fibrosis, and pulmonary arterial hypertension (92,310,333,338,364,445,449,576). MAS has been detected in the epithelium and bronchial smooth muscle, suggesting sites where the beneficial actions of ANG-(1-7) may occur (148,338).…”

“…ulates cell survival, inhibiting alveolar epithelial cell (AEC) apoptosis, a critical event that initiates and propagates lung fibrotic disease. It decreases AEC apoptosis through pathways including the inhibition of JNK activation (312), reduction of endoplasmic reticulum (ER) stress-induced apoptosis (549), inhibition of LPS-induced ADAM17 shedding activity (333), and the upregulation of MAPK phosphatase-2 (219). Altogether, these findings indicate that this peptide may hold therapeutic potential in the treatment of lung fibrosis.…”

Angiotensin-(1–7) attenuates caerulein-induced pancreatic acinar cell apoptosis

“…However, little is known about the potential roles of ACE2-Ang-(1-7)-Mas in apoptosis, and its precise method of regulation in any organ system. Various studies have demonstrated that Ang-(1-7) regulates alveolar epithelial cell survival by inhibiting c-Jun N-terminal kinase phosphorylation and apoptosis through the Ang-(1-7) receptor Mas (17)(18)(19)(20). Gaddam et al (12) identified that the Ang II to Ang-(1-7) ratio increased in the pancreas, suggesting dysregulation of RAS in AP as evidenced by altered Ang II/Ang-(1-7) levels induced by the imbalance of ACE/ACE2 activity.…”