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

摘要

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.