Febuxostat Modulates MAPK/NF‐κBp65/TNF‐α Signaling in Cardiac Ischemia‐Reperfusion Injury

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-α, 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-α pathway.

Febuxostat Modulates Oxidative and Apoptotic Pathways in Acute Doxorubicin‑induced Cardiotoxicity: An Experimental Animal Model Study

“…Moreover, the present study showed that febuxostat decreases caspase-3 serum level compared to doxorubicin-treated rats. This results in agreement with the research that showed febuxostat reduced the apoptotic marker, namely caspase-3 compared to doxorubicin-treated rats due to the antiapoptotic effect of febuxostat [25].…”

c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury

“…Pharmacological inhibition of JNK by various synthetic inhibitors, such as AS601245, SP600125, and SR-3306 (Table 1 ), reduces the size of myocardial infarction and attenuates cardiomyocyte apoptosis after ischemia/reperfusion injury (Yue et al, 2000 ; Ferrandi et al, 2004 ; Duplain, 2006 ; Liu et al, 2007 ; Milano et al, 2007 ; Liu et al, 2008 ; Song et al, 2008 ; Shi et al, 2009 , Zhang J. et al, 2009 ; Xu et al, 2011 ; Chambers et al, 2013 ; Khan et al, 2017 ). Introduction of SP600125 into the solution for perfusion of the isolated mouse heart prior to ischemia/reperfusion increases the resistance to opening the mitochondrial permeability transition pore and protects the myocardium against contractile dysfunction and necrosis during ischemia/reperfusion (Zaha et al, 2016 ).…”

“…Febuxostat and allopurinol (xanthine oxidase inhibitors) pretreatment exerts cardioprotective effects in rats subjected to one-stage left anterior descending coronary artery ligation for 45 min followed by a 60-min reperfusion. Suppression of the active JNK and p38 proteins with the rise in ERK1/ERK2 is more prominent after pretreatment with febuxostat in comparison with allopurinol pretreatment (Khan et al, 2017 ).…”

“…This agent is currently studied in phase II clinical trial for acute coronary syndrome. MAPK phosphatase-1 mediates inactivation of JNK when xanthine oxidase and xanthine dehydrogenase activities are attenuated by the pretreatment with febuxostat (Khan et al, 2017 ). Febuxostat exerts cardioprotective effects in experimental animals, subjected ischemia/reperfusion, but, according to FDA, this agent shows an increased risk of heart-related death in patients.…”

β‐Arrestin1 alleviates acute pancreatitis via repression of NF‐κBp65 activation

“…Nuclear factor‐κB is a ubiquitous inducible transcription factor that is responsible for mediating the expression of a large number of genes involved in proliferation, differentiation, inflammation, and tissue injury and repair . NF‐κB is inactive and resides the cytoplasm.…”