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.

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

Key Laboratory of Targeted Intervention of Cardiovascular Disease,Department of Physiology,Nanjing Medical University,Nanjing 211166,China;Department of Cardiac Surgery,The Second Affiliated Hospital of Nanjing Medical University,Nanjing 211166,China;Department of Rheumatology and Immunology,Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University,Nanjing 211166,China

中国药理学报（英文版）

[1]Chao Ye;Zhi Geng;Ling-li Zhang;Fen Zheng;Ye-bo Zhou;Guo-qing Zhu;Xiao-qing Xiong-.Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory,anti-oxidative and anti-proliferative effects)[J].中国药理学报（英文版）,2022(10):2573-2584

ELABELA,WKYs,minipump

Chronic,infusion,alleviates,vascular,remodeling,spontaneously,hypertensive,rats,anti,inflammatory,oxidative,proliferative,effects,Inflammatory,activation,stress,promote,proliferation,smooth,muscle,cells,VSMCs,which,accounts,pathological,hypertension,second,endogenous,ligand,angiotensin,receptor,like,APJ,that,has,been,discovered,thus,far,this,study,investigated,whether,regulated,SHRs,We,showed,compared,Wistar,Kyoto,expression,was,markedly,decreased,Exogenous,significantly,inhibited,cytokines,NADPH,oxidase,reactive,oxygen,species,production,increased,nuclear,translocation,erythroid,related,Nrf2,Osmotic,exogenous,weeks,diastolic,blood,pressure,alleviated,ameliorated,inflammation,Ang,induced,were,attenuated,by,pretreatment,but,exacerbated,knockdown,Moreover,matrix,metalloproteinase,both,treated,further,revealed,inhibition,PI3K,Akt,signaling,amplified,inhibitor,LY294002,while,antagonist,F13A,abolished,conclusion,demonstrate,through,indicating,may,therapeutic,agent,treating

0.44482