Khajah Maitham A, Hawai Sana, Barakat Ahmad
College of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.
Int J Mol Sci. 2025 Jun 17;26(12):5784. doi: 10.3390/ijms26125784.
A growing body of evidence suggests the potent anti-inflammatory properties of the newly discovered arm of the renin-angiotensin-aldosterone system, ACE2/Ang-(1-7)/MasR, in various disease conditions. Our group was the first to report the anti-inflammatory properties of the Ang-(1-7) polypeptide in the murine dextran sulfate sodium (DSS) colitis model. Both its short half-life and high degradation rate limit the clinical use of Ang-(1-7). One way to compensate for these limitations is through the use of the non-peptide MasR agonist AVE0991. Herein, we aimed to study the anti-inflammatory effects of AVE0991 using the DSS model and the possible synergistic effects with other clinically available medications. Colitis severity was determined using both prophylactic and treatment approaches by gross anatomical and histological assessments and daily weight changes. The colonic expression level/activity of various pro-inflammatory and adhesion molecules was determined by western blotting, immunofluorescence, and proteomic profiling. We showed that AVE0991 treatment significantly reduced colitis severity more effectively with the prophylactic than the treatment approach. An additive anti-inflammatory effect was observed in the combination regimen with AVE0991 plus azathioprine, which was mediated through an increased colonic expression level of mucins and focal adhesion kinase, decreased colonic activity of p38 MAPK and Akt, and decreased colonic expression level of various pro-inflammatory mediators. In conclusion, these data suggest a promising potential for the non-peptide MasR agonist AVE0991 in the treatment of inflammatory bowel disease.
越来越多的证据表明，肾素-血管紧张素-醛固酮系统新发现的分支ACE2/Ang-(1-7)/MasR在各种疾病状态下具有强大的抗炎特性。我们小组是第一个在小鼠葡聚糖硫酸钠（DSS）结肠炎模型中报道Ang-(1-7)多肽抗炎特性的。Ang-(1-7)的短半衰期和高降解率限制了其临床应用。弥补这些限制的一种方法是使用非肽类MasR激动剂AVE0991。在此，我们旨在使用DSS模型研究AVE0991的抗炎作用以及与其他临床可用药物可能的协同作用。通过大体解剖和组织学评估以及每日体重变化，采用预防和治疗方法来确定结肠炎的严重程度。通过蛋白质印迹、免疫荧光和蛋白质组分析来确定各种促炎和黏附分子的结肠表达水平/活性。我们发现，与治疗方法相比，AVE0991预防治疗能更有效地显著降低结肠炎严重程度。在AVE0991加硫唑嘌呤的联合治疗方案中观察到了相加的抗炎作用，这是通过增加黏蛋白和黏着斑激酶的结肠表达水平、降低p38丝裂原活化蛋白激酶和Akt的结肠活性以及降低各种促炎介质的结肠表达水平来介导的。总之，这些数据表明非肽类MasR激动剂AVE0991在治疗炎症性肠病方面具有广阔的应用前景。
