Febuxostat Modulates MAPK/NF-κ Bp65/TNF-α Signaling in Cardiac Ischemia-Reperfusion Injury

Sana Irfan Khan, Rajiv Kumar Malhotra, Neha Rani, Anil Kumar Sahu, Ameesha Tomar, Shanky Garg, Tapas Chandra Nag, Ruma Ray, Shreesh Ojha, Dharamvir Singh Arya, Jagriti Bhatia

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35 Citations (Scopus)

Abstract

Xanthine oxidase and xanthine dehydrogenase have been implicated in producing myocardial damage following reperfusion of an occluded coronary artery. We investigated and compared the effect of febuxostat and allopurinol in an experimental model of ischemia-reperfusion (IR) injury with a focus on the signaling pathways involved. Male Wistar rats were orally administered vehicle (CMC) once daily (sham and IR + control), febuxostat (10 mg/kg/day; FEB10 + IR), or allopurinol (100 mg/kg/day; ALL100 + IR) for 14 days. On the 15th day, the IR-control and treatment groups were subjected to one-stage left anterior descending (LAD) coronary artery ligation for 45 minutes followed by a 60-minute reperfusion. Febuxostat and allopurinol pretreatment significantly improved cardiac function and maintained morphological alterations. They also attenuated oxidative stress and apoptosis by suppressing the expression of proapoptotic proteins (Bax and caspase-3), reducing TUNEL-positive cells, and increasing the level of antiapoptotic proteins (Bcl-2). The MAPK-based molecular mechanism revealed suppression of active JNK and p38 proteins concomitant with the rise in ERK1/ERK2, a prosurvival kinase. Additionally, a reduction in the level of inflammatory markers (TNF-alpha;, IL-6, and NF-κB) was also observed. The changes observed with febuxostat were remarkable in comparison with those observed with allopurinol. Febuxostat protects relatively better against IR injury than allopurinol by suppressing inflammation and apoptosis mediating the MAPK/NF-κBp65/TNF-alpha; pathway.

Original languageEnglish
Article number8095825
JournalOxidative medicine and cellular longevity
Volume2017
DOIs
Publication statusPublished - 2017

ASJC Scopus subject areas

  • Biochemistry
  • Ageing
  • Cell Biology

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