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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.

Myocardial remodeling serves an important role in the pathophysiology of coronary heart disease. The angiotensin-converting enzyme (ACE)2-angiotensin-(1-7) [Ang (1‑7)]‑Mas receptor (MasR) axis is a key regulator in myocardial remodeling and development of heart failure. To investigate how ACE2‑Ang‑(1‑7)‑MasR axis function on myocardial remodeling and cardiac fibrosis in post‑myocardial infarction (MI), male Sprague‑Dawley rats (weight, 200±20 g) were used to establish the model of myocardial infarction by ligating the left coronary artery. The present study suggests that telmisartan (Tel) and olmesartan (Olm) (5 mg/kg/d) can inhibit myocardial remodeling of post‑myocardial infarction through the ACE2‑Ang (1‑7)‑MasR pathway. Administration of Tel or Olm was demonstrated to significantly inhibit collagen deposition using Masson staining. In addition, telmisartan and olmesartan was indicated to antagonize angiotensin II (Ang II) and upregulate ACE2, MasR, Ang (1‑7) expression in myocardial tissue using immunoassay and ELISA test, and the effect of Olm was more marked than that of Tel at the same dosage. Simultaneously, compared with the MI or Sham group, the mRNA and protein expression of ACE2, Ang II and MasR in myocardial tissue demonstrated a remarkable increase in the Olm group, when compared with the Tel group. Taken together, our data demonstrated that ACE2‑Ang (1‑7)‑MasR axis may present a potential protective role in the development of myocardial remodeling and may provide a new target for drug development of cardiac fibrosis. In conclusion, Olm is superior to Tel in inhibiting myocardial local Ang II level reducing myocardial collagen deposition and improving myocardial remodeling by upregulating the expression of ACE2, Ang (1‑7) and MasR.