ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1678921
Candesartan preserves aortic structure and function in cisplatin-treated rats by upregulating SIRT1/Nrf2/HO-1 and suppressing oxidative stress, TLR-4/NF-κB signaling, and necroptosis
Provisionally accepted
Ayman M. Mahmoud1*
Sulaiman Alnasser2
Omnia A M Abd El-Ghafar3Reem S Alruhaimi4
Hanan S Althagafy5
Ahmed Atwa6Emad H M Hassanein7- 1Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, United Kingdom
- 2Qassim University, Buraydah, Saudi Arabia
- 3Nahda University, Beni Suef, Egypt
- 4Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
- 5University of Jeddah, Jeddah, Saudi Arabia
- 6Egyptian Russian University, Badr City, Egypt
- 7Al-Azhar University, Nasr City, Egypt
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Background: Cisplatin (CIS) is widely used in the treatment of several tumors. However, its use is associated with toxicity that contributes to long-term cardiovascular complications in cancer survivors. This study investigated whether the angiotensin II receptor blocker candesartan (CAN) could protect against CIS-induced aortic injury in rats. Methods: Rats received CAN (5 mg/kg, oral) for 10 days, with a single intraperitoneal dose of CIS (7 mg/kg) administered on day 7. Results: Histopathological analysis revealed that CIS induced extensive aortic damage, including endothelial disruption, elastic fiber fragmentation, thrombi, and medial calcification, which were significantly alleviated by CAN. CIS-induced oxidative stress was evidenced by elevated lipid peroxidation, myeloperoxidase (MPO) activity, and suppressed antioxidant defenses, while inflammatory activation was marked by upregulation of TLR-4, NF-κB, iNOS, and pro-inflammatory cytokines. CAN treatment reversed these alterations and restored redox balance and anti-inflammatory cytokine IL-10 levels. CAN enhanced SIRT1/Nrf2/HO-1 signaling and suppressed necroptosis-associated proteins (RIP1, RIP3, MLKL, and caspase-8). Molecular docking supported direct interactions between CAN and SIRT1, Keap1, and HO-1. Additionally, CAN corrected the CIS-induced imbalance in the renin-angiotensin system by decreasing angiotensin (Ang) II and increasing Ang-(1–7), and preserved endothelium-dependent vasorelaxation. Conclusion: These findings suggest that CAN protects against CIS-induced vascular injury through coordinated suppression of oxidative stress, inflammation, and necroptosis, alongside upregulation of SIRT1/Nrf2/HO-1 and restoration of vascular function. CAN may represent a promising vascular-protective strategy in patients undergoing CIS chemotherapy.
Keywords: candesartan, Cisplatin, vascular injury, Oxidative Stress, Inflammation
Received: 03 Aug 2025; Accepted: 17 Sep 2025.
Copyright: © 2025 Mahmoud, Alnasser, Abd El-Ghafar, Alruhaimi, Althagafy, Atwa and Hassanein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ayman M. Mahmoud, ayman.mahmoud@science.bsu.edu.eg
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