Abstract：
Sepsis induced myocardial dysfunction (SIMD) is a serious complication of sepsis. There is increasing evidence that the renin-angiotensin system (RAS) is activated in SIMD. Angiotensinogen (AGT) is a precursor of the RAS, and the inhibition of AGT may have significant cardiovascular benefits. But until now, there have been no reports of small molecule drugs targeting AGT. In this study, we designed a promoter-luciferase based system to screen for novel AGT inhibitors to alleviate SIMD. As a result of high-throughput screening, a total of 5 compounds from 351 medicinal herb-derived natural compounds were found inhibiting AGT. 18β-glycyrrhetinic acid (18βGA) was further identified as a potent suppressor of AGT. In vitro experiments, 18βGA could inhibit the secretion of AGT by HepG2 cells and alleviate the elevated level of mitochondrial oxidative stress in cardiomyocytes co-cultured with HepG2 supernatants. In vivo, 18βGA prolonged the survival rate of SIMD mice, enhanced cardiac function, and inhibited the damage of mitochondrial function and inflammation. In addition, the results showed that 18βGA may reduce AGT transcription by downregulating hepatocyte nuclear factor 4 (HNF4) and that further alleviated SIMD. In conclusion, we provided a more efficient screening strategy for AGT inhibitors and expanded the novel role of 18βGA as a promising lead compound in rescuing cardiovascular disease associated with RAS overactivation.
摘要：
脓毒症心肌功能障碍(SIMD)是脓毒症的严重并发症。有越来越多的证据表明肾素-血管紧张素系统(RAS)在SIMD中被激活。血管紧张素原（AGT）是RAS的前体，和AGT的抑制可能有显著的心血管益处。但直到现在,尚无针对AGT的小分子药物的报道.在这项研究中,我们设计了一种基于启动子-荧光素酶的系统来筛选新型AGT抑制剂以缓解SIMD。作为高通量筛选的结果，从351个草药来源的天然化合物中发现总共5个化合物抑制AGT。18β-甘草次酸(18βGA)被进一步鉴定为AGT的有效抑制剂。体外实验,18βGA可以抑制HepG2细胞分泌AGT，减轻HepG2上清液共培养心肌细胞线粒体氧化应激水平的升高。在体内,18βGA延长了SIMD小鼠的存活率，增强心脏功能，并抑制线粒体功能和炎症的损伤。此外,结果表明，18βGA可能通过下调肝细胞核因子4（HNF4）来降低AGT转录，从而进一步缓解SIMD。总之,我们为AGT抑制剂提供了更有效的筛选策略,并扩展了18βGA作为一种有前景的先导化合物在挽救与RAS过度激活相关的心血管疾病方面的新作用.
