Targeting inflammation and redox perturbations by lisinopril mitigates Freund’s adjuvant-induced arthritis in rats: role of JAK-2/STAT-3/RANKL axis, MMPs, and VEGF

Background: Cardiovascular disorders are major complications of rheumatoid arthritis (RA). Hence, finding effective agents that can target RA progression and its cardiovascular consequences is demanding. The present work aimed to explore the potential of lisinopril, an angiotensin-converting enzyme inhibitor, to mitigate adjuvant’s-induced arthritis with emphasis on the pro-inflammatory signals, articular degradation cues, and angiogenesis alongside JAK-2/STAT-3 and Nrf2/HO-1 pathways. Methods: Lisinopril (10 mg/kg/day) was administered by oral gavage for 3 weeks and the target signals were examined by biochemical assays, ELISA, histopathology, immunoblotting, and immunohistochemistry. Results: Lisinopril attenuated the progression of arthritis as proven by lowering paw edema, arthritic index, and gait scores alongside diminishing the immune-cell infiltration/aberrant histopathology in the dorsal pouch lining. These favorable actions were associated with curtailing the production of inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-17) and the pro-inflammatory angiotensin II alongside upregulating the anti-inflammatory angiotensin-(1–7) in the hind paw of arthritic rats. At the molecular level, lisinopril inhibited the upstream JAK-2/STAT-3 pathway by downregulating the protein expression of p-JAK-2/total JAK-2 and p-STAT-3/total STAT-3 ratio and the nuclear levels of NF-κBp65. Meanwhile, lisinopril curbed the downstream cartilage degradation signals matrix metalloproteinases (MMP-3 and MMP-9) and the bone erosion cue RANKL. Equally important, the protein expression of the angiogenesis signal VEGF was downregulated in the hind paw/dorsal lining. With respect to oxidative stress, lisinopril suppressed the paw lipid peroxides and boosted GSH and Nrf-2/HO-1 pathway. Conclusion: Lisinopril attenuated adjuvant-induced arthritis via inhibition of inflammation, articular degradation cues, and angiogenesis.