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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

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Abstract

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.

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Data availability

Data are available on request to the authors.

Abbreviations

ACE:

Angiotensin-converting enzyme

Ang-(1–7):

Angiotensin-(1–7)

Ang II:

Angiotensin II

CFA:

Complete Freund’s adjuvant

HO-1:

Heme oxygenase-1

IL:

Interleukin

JAK:

Janus kinase

MMP:

Matrix metalloproteinase

NF-κB:

Nuclear factor kappa B

Nrf-2:

Nuclear factor erythroid 2-related factor-2

RANKL:

Receptor activator nuclear factor kappa-B ligand

RA:

Rheumatoid arthritis

ROS:

Reactive oxygen species

STAT:

Signal transducer and activator of transcription

TNF-α:

Tumor necrosis factor-alpha

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The authors are thankful to Taif University Researchers Supporting Project number (TURSP-2020/29), Taif University, Taif, Saudi Arabia. The work was also supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R91), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. We also acknowledge the kind help of Dr. Adel Kholosy (Faculty of veterinary sciences, Cairo University) in Histology/Immunohistochemistry.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia

    Hany H. Arab

  2. Department of Pharmacy, Kut University College, Al Kut, Wasit, 52001, Iraq

    Sarah A. Abd El-Aal

  3. Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Mecca, 21955, Saudi Arabia

    Ahmed M. Ashour

  4. Basic Health Sciences Department, College of Medicine, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia

    Azza A. K. El-Sheikh

  5. Biochemistry Division, College of Pharmacy, Riyadh Elm University, Riyadh, 11681, Saudi Arabia

    Hana J. Al Khabbaz

  6. College of Pharmacy and Health Sciences, Ajman University, 346, Ajman, United Arab Emirates

    El-Shaimaa A. Arafa

  7. Center of Medical and Bio-Allied Health Sciences Research, Ajman University, 346, Ajman, United Arab Emirates

    El-Shaimaa A. Arafa

  8. Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt

    Ayman M. Mahmoud

  9. Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, UK

    Ayman M. Mahmoud

  10. Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, 31527, Egypt

    Ahmed M. Kabel

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  1. Hany H. Arab
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  2. Sarah A. Abd El-Aal
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Correspondence to Hany H. Arab.

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There are no conflicts of interest among authors in the current study.

Ethics approval

All experimental procedures performed on rats were consistent with the instructions of the Guide for Care and Use of Laboratory Animal established by the US National Institutes of Health (Publication No. 85-23, revised 1996). The approval of Taif University Research Ethics Committee was also acquired (Approval ID: 43-016, date: 19th of September 2020).

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Arab, H.H., Abd El-Aal, S.A., Ashour, A.M. et al. 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. Inflammopharmacol 30, 1909–1926 (2022). https://doi.org/10.1007/s10787-022-00998-w

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