Ulinastatin Protects against CVB3-Induced Acute Viral Myocarditis through Nrf2 Activation
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ORIGINAL ARTICLE
Ulinastatin Protects against CVB3-Induced Acute Viral Myocarditis through Nrf2 Activation Fangqiang Song,1 Fanpo Kong,1 Hongqing Zhang,1 Yongqin Zhou,1 and Ming Li
2,3
Inflammation and oxidative stress are implicated in the pathogenesis of acute viral myocarditis (AVM). Ulinastantin (UTI), an inhibitor of serine protease widely used in treatment of pancreatitis and various inflammatory disorders, displays cardioprotective properties in experimental animals. Although the specific mechanism through which UTI regulates cardiac function is not well explored, evidence suggests that UTI might activate nuclear factor E2-related factor 2 (Nrf2) signaling. In this study, we investigated the role of Nrf2 in mediating UTI’s cardioprotection in a mouse model of AVM. We found that UTI is an activator of Nrf2 signaling. It markedly increased Nrf2 nuclear translocation, Nrf2 transcription capacity, and the downstream protein expression. In addition, UTI possessed strong protective functions in coxsackievirus B3 (CVB3)-induced AVM. UTI treatment effectively reduced the cardiac damage, decreased the expression of inflammatory cytokines, and balanced oxidative stress via improving the activity of anti-oxidant and detoxifying enzymes. Even more impressively, UTI achieved its cardioprotective activities in an Nrf2-dependent manner. Taken together, our study has identified a novel pathway through which UTI exerts its cardioprotective functions and provides a molecular basis for UTI potential applications in the treatment of AVM and other inflammatory disorders.
Abstract—
KEY WORDS: ulinastatin; myocarditis; inflammation; oxidative stress; Nrf2.
INTRODUCTION Myocarditis is characterized by the overexpression of inflammatory cytokines and oxidative mediators and is an important cause of sudden death, especially in children and younger patients [4]. It has been reported that viral infection, bacterial infection, rheumatic Fangqiang Song and Fanpo Kong contribute equally to this work. 1
Department of Critical Care Medicine, Tengzhou Central People’s Hospital, Tengzhou, Shandong Province 277500, China 2 Department of Urology, Tengzhou Central People’s Hospital, Tengzhou, Shandong Province 277500, China 3 To whom correspondence should be addressed at Department of Urology, Tengzhou Central People’s Hospital, Tengzhou, Shandong Province 277500, China. E-mail: [email protected]
carditis, and autoimmunity are the major contributors of myocarditis [28, 29]. Coxsackievirus B3 (CVB3) is the most common cause of acute viral myocarditis (AVM) [8, 11, 13]. Naturally, CVB3 is always employed to establish an experimental model of myocarditis [20]. Although many AVM-related studies have been conducted in recent years, the specific pathogenesis of AVM is still unclear. Thus, effective drug and therapeutic methods for AVM have not been found. Ulinastatin (UTI), an inhibitor of serine protease and urinary trypsin, exhibits anti-inflammatory activities in many diseases, such as pancreatitis, pneumonia, and nephritis [3, 16, 34]. In add
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