Ulinastatin Protects against CVB3-Induced Acute Viral Myocarditis through Nrf2 Activation

Abstract

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.

Efficacy of Ulinastatin and Sulforaphane Alone or in Combination in Rat Model of Streptozotocin Diabetes Induced Vascular Dementia

“…UTI reduces the lipid peroxidation as observed by the reduced TBARS levels [ 64 ]. UTI mediated increase in the anti-oxidants (SOD, GSH, CAT) is possibly via upregulation of nuclear factor E2-related factor 2 (Nrf2) gene [ 21 , 22 , 65 ] and activation of Nrf2/NOS pathway [ 66 ]. Also, UTI administration regulates AMPK/NF-kB pathway, and downregulates (toll like receptor) TLR 4 which are further reported to decreases inflammation [ 67 ].…”

The Nrf-2/HO-1 Signaling Axis: A Ray of Hope in Cardiovascular Diseases

“…As ferroptosis can have an effect on cardiovascular diseases, it is closely related to clockophagy; we suggest that there is a relationship between cardiovascular diseases and clockophagy. [35]. Furthermore, Ai et al revealed that Nrf2 pathway is downregulated because of the upregulation of the 12/15-lipoxygenase (12/15-LO), which can be inhibited by baicalein through reducing inflammatory cytokine production and oxidative stress [35,36].…”

“…[35]. Furthermore, Ai et al revealed that Nrf2 pathway is downregulated because of the upregulation of the 12/15-lipoxygenase (12/15-LO), which can be inhibited by baicalein through reducing inflammatory cytokine production and oxidative stress [35,36]. Conversely, Wang et al have demonstrated that the immune and inflammatory processes can also function as a trigger for the activation of Nrf2 [37].…”

Chitoheptaose Promotes Heart Rehabilitation in a Rat Myocarditis Model by Improving Antioxidant, Anti-Inflammatory, and Antiapoptotic Properties

“…Myocarditis involves many myocardial inflammatory diseases, such as acute myocarditis, chronic myocarditis, and inflammatory cardiomyopathies, and inflammatory diseases with cardiomyopathies [5]. Oxidative stress is also an important risk in the pathogenesis of myocarditis [6]. Inflammatory and oxidative stress can affect the left ventricular internal diameter in end diastole (LVIDd) and left ventricular internal diameter in end systole (LVIDs) [7].…”