Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory,anti-oxidative and anti-proliferative effects  

作　　者：Chao Ye Zhi Geng Ling-li Zhang Fen Zheng Ye-bo Zhou Guo-qing Zhu Xiao-qing Xiong 

机构地区：[1]Key Laboratory of Targeted Intervention of Cardiovascular Disease,Department of Physiology,Nanjing Medical University,Nanjing 211166,China [2]Department of Cardiac Surgery,The Second Affiliated Hospital of Nanjing Medical University,Nanjing 211166,China [3]Department of Rheumatology and Immunology,Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University,Nanjing 211166,China

出　　处：《Acta Pharmacologica Sinica》2022年第10期2573-2584,共12页中国药理学报（英文版）

基　　金：This work was supported by National Nature Science Foundation of China(81600323&81970356).

摘　　要：Inflammatory activation and oxidative stress promote the proliferation of vascular smooth muscle cells(VSMCs),which accounts for pathological vascular remodeling in hypertension.ELABELA(ELA)is the second endogenous ligand for angiotensin receptor-like 1(APJ)receptor that has been discovered thus far.In this study,we investigated whether ELA regulated VSMC proliferation and vascular remodeling in spontaneously hypertensive rats(SHRs).We showed that compared to that in Wistar-Kyoto rats(WKYs),ELA expression was markedly decreased in the VSMCs of SHRs.Exogenous ELA-21 significantly inhibited inflammatory cytokines and NADPH oxidase 1 expression,reactive oxygen species production and VSMC proliferation and increased the nuclear translocation of nuclear factor erythroid 2-related factor(Nrf2)in VSMCs.Osmotic minipump infusion of exogenous ELA-21 in SHRs for 4 weeks significantly decreased diastolic blood pressure,alleviated vascular remodeling and ameliorated vascular inflammation and oxidative stress in SHRs.In VSMCs of WKY,angiotensin II(Ang II)-induced inflammatory activation,oxidative stress and VSMC proliferation were attenuated by pretreatment with exogenous ELA-21 but were exacerbated by ELA knockdown.Moreover,ELA-21 inhibited the expression of matrix metalloproteinase 2 and 9 in both SHR-VSMCs and Ang II-treated WKY-VSMCs.We further revealed that exogenous ELA-21-induced inhibition of proliferation and PI3K/Akt signaling were amplified by the PI3K/Akt inhibitor LY294002,while the APJ receptor antagonist F13A abolished ELA-21-induced PI3K/Akt inhibition and Nrf2 activation in VSMCs.In conclusion,we demonstrate that ELA-21 alleviates vascular remodeling through anti-inflammatory,anti-oxidative and anti-proliferative effects in SHRs,indicating that ELA-21 may be a therapeutic agent for treating hypertension.

关 键 词：ELABELA peptide HYPERTENSION proliferation vascular remodeling inflammation oxidative stress 

分 类 号：R285.5[医药卫生—中药学]