Details

Autor(en) / Beteiligte

• Mohamad, Hoda E.
• Askar, Mervat E.
• Shaheen, Mohamed A.
• Baraka, Nourhan M.
• Mahmoud, Yasmin K.

Titel

Sacubitril/valsartan alleviates sunitinib-induced cardiac fibrosis and oxidative stress via improving TXNIP/TRX system and downregulation of NF-ĸB/Wnt/β-catenin/SOX9 signaling

Ist Teil von

• International immunopharmacology, 2024-05, Vol.132, p.111963-111963, Article 111963

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2024

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• [Display omitted] •Sunitinib causes several cardiovascular toxicities such as cardiac fibrosis.•Sunitinib induces oxidative stress via disruption of TXNIP/TRX system.•Sunitinib worsens cardiac fibrosis by upregulation of NF-ĸB/Wnt/β-catenin/SOX9.•Sacubitril/valsartan alleviates sunitinib-induced cardiac fibrosis. We aimed in this study to investigate the possible cardioprotective effects of sacubitril/valsartan against sunitinib-induced cardiac fibrosis (CF) and oxidative stress via targeting thioredoxin-interacting protein/thioredoxin (TXNIP/TRX) system and nuclear factor-kappa B (NF-κB)/Wingless-related MMTV integration site (Wnt)/β-catenin/Sex-determining region Y box 9 (SOX9) signaling. CF was induced in male Wistar albino rats by cumulative dose of sunitinib (300 mg/kg, given over 4 weeks as: 25 mg/kg orally, three times a week), which were co-treated with sacubitril/valsartan (68 mg/kg/day, orally) for four weeks. Significant elevation in blood pressure, cardiac inflammatory and fibrotic markers besides cardiac dysfunction were observed. These alterations were associated with disruption of TXNIP/TRX system, upregulation of NF-κB/Wnt/β-catenin/SOX9 pathway along with marked increase in lysyl oxidase (LOX) and matrix metalloproteinase-1 (MMP-1) expressions and extensive deposition of collagen fibers in cardiac tissues. Luckily, sacubitril/valsartan was able to reverse all of the aforementioned detrimental effects in sunitinib-administered rats. These findings illustrate a potential role of sacubitril/valsartan in alleviating CF and oxidative stress induced by sunitinib via antioxidant, anti-inflammatory and antifibrotic properties. These remarkable effects of sacubitril/valsartan were mediated by its ability to improve TXNIP/TRX system and downregulate NF-κB/Wnt/β-catenin/SOX9 signaling in addition to decreasing LOX and MMP-1 expressions in cardiac tissues. In summary, this study highlights sacubitril/valsartan as a potential therapeutic agent in mitigating CF and oxidative stress especially in cancer cases treated with sunitinib.