Anti-hypertension effect of Wuwei Jiangya decoction via ACE2/Ang1-7/ MAS signaling pathway in SHR based on network degree-distribution analysis

Ethnopharmacological relevance: Wuwei Jiangya decoction (WJD) is a traditional Chinese medicinal formula (Fangji) composed of Gastrodiae Rhizoma, Chuanxiong Rhizoma, Puerariae Lobatae Radix, Cyathulae Radix, and Achyranthis Bidentatae Radix, all of which have been verified to combat hypertension. However, the integrative "shot-gun" mechanism of WJD and its primary active ingredients are still unclear.Aim of the study: To investigate the anti-hypertensive effects of WJD and its originating ingredients.Methods: Network-based degree distribution analysis combined with in vivo experiments were performed.Results: A total of 144 active ingredients in WJD were identified to regulate 84 hypertension-related targets, which are mainly involved in blood pressure and blood vessel diameter regulation. However, for the antihypertension effects, "more does not mean better". The majority (76%) of the hubs in the H-network were regulated by no more than four ingredients. We identified 16 primary ingredients that accounted for the therapeutic action against hypertension. For compatibility, the five herbs consistently focused on blood pressure, vascular diameter, and angiogenesis, with the renin-angiotensin system as a primary target. The characteristics of each herb were involved in processes such as lipid localization and oxidative stress, which interact to constitute the regulatory network targeting hypertension, its risk factors, and organ damage. In vivo, WJD significantly reduced systolic blood pressure (SBP), improved left ventricular mass index, and ameliorated cardiac hypertrophy and vascular injury by moderating the renin-angiotensin system via activating the ACE2/Ang-(1-7)/Mas signaling pathway.Conclusion: WJD can lower SBP and ameliorate cardiac hypertrophy and vascular injury through the ACE2/Ang(1-7)/Mas pathway, thus providing new insights into the development of traditional Chinese medicine as a therapeutic agent for hypertension.