Ulinastatin Protects against CVB3-Induced Acute Viral
Myocarditis through Nrf2 Activation
and Ming Li
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 prop-
erties in experimental animals. Although the specific mechanism through which UTI regu-
lates 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 transcrip-
tion 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.
KEY WORDS: ulinastatin; myocarditis; inflammation; oxidative stress; Nrf2.
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 . It has been reported
that viral infection, bacterial infection, rheumatic
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 .
Although many AVM-related studies have been con-
ducted in recent years, the specific pathogenesis of
AVM is still unclear. Thus, effective drug and therapeu-
tic methods for AVM have not been found.
Ulinastatin (UTI), an inhibitor of serine protease
and urinary trypsin, exhibits anti-inflammatory activi-
ties in many diseases, such as pancreatitis, pneumonia,
and nephritis [3, 16, 34]. In addition, UTI also has
cardioprotective functions in myocardial damage .
However, the effect of UTI on AVM and the underlying
mechanism remains unclear.
Fangqiang Song and Fanpo Kong contribute equally to this work.
Department of Critical Care Medicine, Tengzhou Central People’s Hos-
pital, Tengzhou, Shandong Province 277500, China
Department of Urology, Tengzhou Central People’s Hospital, Tengzhou,
Shandong Province 277500, China
To whom correspondence should be addressed at Department of Urolo-
gy, Tengzhou Central People’s Hospital, Tengzhou, Shandong Province
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Inflammation, Vol. 41, No. 3, June 2018 (