Angiotensin-(1-7) Ameliorates Collagen-induced Articular And Cardiac Injury Via Anti-inflammatory Activity In Arthitis Mouse Models

Objective: It is reported that the angiotensin converting enzyme 2-angiotensin-(1-7)-Mas axis(ACE2-Ang-(1-7)-Mas axis)participate in the development and progression of rheumatoid arthritis and cardiovascular complications.We supposed that the inhibitory effect of Ang-(1-7)on the destruction of articular bone by inhibition NF-κB and MAPKs inflammatory signaling pathway to reduce the release of inflammatory factor.Ang-(1-7)plays an anti-inflammatory role in protecting the heart.Methods: 60 Male DBA/1 mice were divided into six groups,randomly: Control group(normal mouse+normal saline),CIA group(collagen-induced arthritis mouse+normal saline),CIA+Ang-(1-7)group 【collagen-induced arthritis mouse+Ang-(1-7)】,CIA+AVE0991 group(collagen-induced arthritis mouse+AVE0991),Ang-(1-7)group 【normal mouse+Ang-(1-7)】,AVE0991 group(normal mouse+AVE0991).After 28 days of feeding,Each group of mice was injected intraperitoneally with normal saline,Ang-(1-7)or AVE0991,and injected once a day for one week.Mouse paw thickness was measured and scored on the severity of arthritis by Scoring system.Blood was collected to measure serum CRP,TNF-α,IL-1β and IL-6 levels.The ankle joint and heart structure was examined via hematoxylin-eosin(HE)staining.The cardiac fibrosis was examined via Masson staining.Expression levels of RANKL and MMP3 in ankle were evaluated using immunohistochemical,real-time PCR.Protein expression levels of NF-κB、IκB-α、p-p38、p38、p-ERK、ERK、p-JNK、JNK in ankle and α-SMA in heart were evaluated using Western blot.Results: High inflammation status is induced by collagen in mice,leading to articular and cardiac injury.Treatment with Ang-(1-7)reduces the release of inflammatory factor by inhibiting NF-κB and MAPKs inflammatory signaling pathway and leads to a downregulation of RANKL and MMP3,alleviating the destruction of articular bone.Treatment with Ang-(1-7)protects the heart in a state of inflammation.Conclusions:(1)Collagen can induce hyper-inflammation articular injury in mice.(2)Collagen can induce cardiac hyper-inflammation and cardiac injury in mice.(3)It is proved that Ang-(1-7)can alleviate Arthritis and improve articular injury by inhibiting NF-κB and MAPKs inflammatory signaling pathway via Mas receptor.(4)It is proved that Ang-(1-7)can improve cardiac injury by inhibiting cardiac inflammation and fibrosis in Mas receptor.