AUTHOR=Wang Zhongjie , Huang Wenhan , Ren Feifeng , Luo Lei , Zhou Jun , Huang Dongmei , Jiang Mei , Du Huaan , Fan Jinqi , Tang Lin 

TITLE=Characteristics of Ang-(1–7)/Mas-Mediated Amelioration of Joint Inflammation and Cardiac Complications in Mice With Collagen-Induced Arthritis

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.655614

DOI=10.3389/fimmu.2021.655614

ISSN=1664-3224

ABSTRACT=<sec><title>Objectives</title><p>Rheumatoid arthritis (RA) is a disabling disease with a high incidence that is regularly accompanied by cardiovascular complications. Several studies have suggested that renin–angiotensin–aldosterone system (RAAS) is closely associated with RA. The aim of this study was to investigate the mechanisms underlying Angiotensin-(1–7) [Ang-(1–7)] and its Mas receptor agonist (AVE0991) on joint inflammation and cardiac complications in a collagen-induced arthritis (CIA) model.</p></sec><sec><title>Methods</title><p>Collagen type II was injected into DBA/1 mice to construct an arthritis model. CIA mice were treated with Ang-(1–7) (2.0 mg/kg intraperitoneally) and AVE0991 (3.0 mg/kg intraperitoneally). The serum levels of inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 β, IL-6, and C-reactive protein (CRP)] were determined by ELISA. The mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-<italic>κ</italic>B) signaling pathways in joint tissues and the transforming growth factor (TGF)-<italic>β</italic>/Smad pathway and levels of <italic>α</italic>-Smooth muscle action (SMA) and <italic>β</italic>-myosin heavy chain (MHC) protein expression in cardiac tissues were assessed by western blots. The levels of TGF-<italic>β</italic>/Smad pathway, <italic>α</italic>-SMA, and <italic>β</italic>-MHC RNA in cardiac tissues were analyzed by real time-PCR. The levels of receptor activator of nuclear factor kappa ligand (RANKL) and promoting matrix metalloproteinase (MMP)-3 expression in the ankle joints were detected by immunohistochemistry and real time-PCR.</p></sec><sec><title>Results</title><p>Ang-(1–7) and AVE0991 reduced the levels of inflammatory cytokines and inhibited the MAPKs and NF-<italic>κ</italic>B signaling pathways in ankle joint tissues, reduced RANKL and MMP3 expression, and ameliorated local joint inflammation and bone destruction compared with the control group. In addition, Ang-(1–7) and AVE0991 attenuated the TGF-<italic>β</italic>/Smad signaling pathway, reduced the levels of <italic>α</italic>-SMA and <italic>β</italic>-MHC expression, and diminished inflammatory cell infiltration into the myocardial interstitium and myocardial interstitial fibrosis in the hearts of CIA mice.</p></sec><sec><title>Conclusions</title><p>Ang-(1–7) alleviated joint damage caused by inflammation likely through the attenuation of NF-<italic>κ</italic>B and MAPK pathways and ameliorated inflammation-induced cardiac fibrosis and activation of the TGF-<italic>β</italic>/Smad pathway. Moreover, Ang-(1–7) was likely mediated through the Mas receptor. This study provides theoretical evidence for exploring novel clinical therapeutic approaches for RA and its cardiac complications.</p></sec>