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

Objectives: 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.

Methods: 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-B) signaling pathways in joint tissues and the transforming growth factor (TGF)-/Smad pathway and levels of -Smooth muscle action (SMA) and -myosin heavy chain (MHC) protein expression in cardiac tissues were assessed by western blots. The levels of TGF-/Smad pathway, -SMA, and -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.

Results: Ang-(1-7) and AVE0991 reduced the levels of inflammatory cytokines and inhibited the MAPKs and NF-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-/Smad signaling pathway, reduced the levels of -SMA and -MHC expression, and diminished inflammatory cell infiltration into the myocardial interstitium and myocardial interstitial fibrosis in the hearts of CIA mice.

Conclusions: Ang-(1-7) alleviated joint damage caused by inflammation likely through the attenuation of NF-B and MAPK pathways and ameliorated inflammation-induced cardiac fibrosis and activation of the TGF-/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.