Abstract
ObjectivesRheumatoid 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.MethodsCollagen 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-κB) signaling pathways in joint tissues and the transforming growth factor (TGF)-β/Smad pathway and levels of α-Smooth muscle action (SMA) and β-myosin heavy chain (MHC) protein expression in cardiac tissues were assessed by western blots. The levels of TGF-β/Smad pathway, α-SMA, and β-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.ResultsAng-(1–7) and AVE0991 reduced the levels of inflammatory cytokines and inhibited the MAPKs and NF-κB 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-β/Smad signaling pathway, reduced the levels of α-SMA and β-MHC expression, and diminished inflammatory cell infiltration into the myocardial interstitium and myocardial interstitial fibrosis in the hearts of CIA mice.ConclusionsAng-(1–7) alleviated joint damage caused by inflammation likely through the attenuation of NF-κB and MAPK pathways and ameliorated inflammation-induced cardiac fibrosis and activation of the TGF-β/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.
Highlights
Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease that is mainly characterized by proliferation of synovial cells and erosion of articular cartilage and bone (1)
The CRP, TNF-a, IL-1b, and IL-6 levels in the serum of CIA+ Ang-(1–7) and CIA + AVE0991 mice were significantly reduced compared to the CIA group (Figures 1A–D)
Ang-(1–7) and AVE0991 Relieved Swelling in the Paws of CIA Mice and Reduced the Arthritic Index
Summary
Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease that is mainly characterized by proliferation of synovial cells and erosion of articular cartilage and bone (1). During the initiation and progression of RA, the articular synovial tissues are infiltrated with inflammatory cells, and subsequently secrete inflammatory cytokines, such as TNFa, IL-1, IL-6 (3). A previous study has shown that the antiarthritic effect is produced via inhibiting TNF-a and IL-1 and up-regulating anti-inflammatory mediators in the knee tissue of CIA mice (4). IL-6 activates inflammatory cells to enter the synovial membrane and propagate the inflammatory response (5), so inhibition of IL-6/IL-17A can potentially reduce joint inflammation and cartilage destruction of RA onset (6). The inhibition of NF-kB activity suppresses joint inflammation in mouse model of CIA (6). MMP production by synovial fibroblasts leads to articular cartilage destruction and joint deformity (10). Inflammatory factors activate the TGF-b/Smad signaling pathway, which enhance the production of collagen and extracellular matrix by myocardial fibroblasts leading to myocardial fibrosis (11)
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