Interaction of N‐acetyl‐seryl‐aspartyl‐lysyl‐proline with the angiotensin‐converting enzyme 2–angiotensin‐(1–7)–Mas axis attenuates pulmonary fibrosis in silicotic rats

Abstract

New Findings What is the central question of this study?What are the effects of the antifibrotic peptide acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) on the angiotensin‐converting enzyme 2 (ACE2)–angiotensin‐(1–7)–Mas axis during the occurrence and progression of silicosis? What is the main finding and its importance?Ac‐SDKP inhibited lung fibrosis in rats exposed to silica by activation of the ACE2–angiotensin‐(1–7)–Mas axis. Angiotensin‐(1–7) potentially promotes Ac‐SDKP by increasing the level of meprin α, the major synthetase of Ac‐SDKP. Thus, the interaction Ac‐SDKP and angiotesin‐(1–7) in silicosis could provide a new therapeutic strategy. Abstract The central role of angiotensin‐converting enzyme (ACE) in the occurrence and progression of silicosis has been established. The antifibrotic peptide acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) can be degraded by ACE. The ACE2–angiotensin‐(1–7)–Mas axis is protective and acts to counterbalance the detrimental effects of ACE–angiotensin II (Ang II)–Ang II type 1 receptor and exerts antifibrotic effects. Here, we demonstrate an interaction between Ac‐SDKP and Ang‐(1–7) in the inhibition of collagen deposition and myofibroblast differentiation in rats exposed to silica. Treatment with Ac‐SDKP increased the level of ACE2–Ang‐(1–7)–Mas in rats or in cultured fibroblasts and decreased the levels of collagen type I and α‐smooth muscle actin. Furthermore, exogenous Ang‐(1–7) had similar antifibrotic effects and increased the level of meprin α, a major Ac‐SDKP synthetase, both in vivo and in vitro. Compared with non‐silicotic patients exposed to silica, the level of serum ACE was increased in patients with silicosis phase III; the levels of Ang II and Ang‐(1–7) were high in patients with silicosis phase II; and the level of Ac‐SDKP was high in the silicosis phase III group. These data imply that Ac‐SDKP and Ang‐(1–7) have an interactive effect as regulatory peptides of the renin–angiotensin system and exert antifibrotic effects.

<p>ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica</p>

“…Immunostaining for α-smooth muscle actin (α-SMA, EPR5368; Epitomics, Burlingame, CA, USA) was performed on lung sections as described previously. 8,9 Brown staining indicated samples positive for α-SMA expression.…”

“…7 Our recent studies also showed that Ac-SDKP (N-acetyl-seryl-aspartyl -lysyl-proline) exerts an anti-silicotic effect through activation of the ACE2-Ang-(1-7)-Mas axis. 8,9 Our previous study found that the expression of ACE, Ang II and AT1 increased while that of ACE2 decreased in local lung tissue in mice with acute lung injury induced by limb ischemia-reperfusion. After preventive intervention with DIZE for 4 weeks, the lesions of the lung injury were attenuated, and the production of Ang-(1-7) and Mas receptor protein were up-regulated in the lung, whereas the opposite trend was observed for Ang II and the AT1 receptor protein.…”

“…10 Moreover, we observed high ACE2 expression in the epithelial cells of the lung, and ACE2 inhibited myofibroblast differentiation induced by Ang II in fibroblasts. 8 We, therefore, hypothesized that increased ACE2 expression may have a beneficial effect on alveolar epithelial cells. Several studies have shown that diminazene aceturate (DIZE) is an activator of ACE2 and that treatment with DIZE is beneficial for myocardial, liver, and biliary fibrosis in mice.…”

Overview of lethal human coronaviruses

“…69 The structure of the S protein consists of four parts: an SP located at the N terminus (amino acids 1-12), an extracellular domain (amino acids 13-1195), a TM domain (amino acids 1196-1215), and an intracellular domain (amino acids 1216-1255). 16 The S1 subunit contains two independent domains, an N-terminal domain (NTD, amino acids 18-353) 70 and a C-terminal domain (amino acids 367-588), both of which may function as receptor-binding domains (RBDs); 71 these domains serve as critical targets for the development of vaccines and therapeutics 72,73 and facilitate the involvement of the S1 subunit in cell receptor (DPP4) binding. The core structure of the MERS-CoV S protein RBD is a five-stranded antiparallel sheet with several short helices, in which three disulfide bonds stabilize the core by connecting C383 to C407, C425 to C478, and C437 to C585.…”

Could SARS-CoV-2-induced lung injury be attenuated by vitamin D?

“…ARDS and acute lung injury are associated with damaged pulmonary microvascular endothelial cells (PMVECs), which result in increased alveolar permeability and pulmonary oedema ( Su et al, 2004 ). The balance between the expression of ACE1 and ACE2 is closely related to the ratio of Ang Ⅱ:Ang1-7, and an imbalance of Ang Ⅱ:Ang1-7 can lead to acute lung injury ( Gao et al, 2019 , Queiroz-Junior et al, 2019 , Wang et al, 2018 ).…”