Abstract
The present study was performed to explore whether and how impaired autophagy could modulate calcium/calmodulin-dependent protein kinase II (CAMKII)-regulated necrosis in the pathogenesis of acute pancreatitis (AP). Wistar rats and AR42J cells were used for AP modeling. When indicated, genetic regulation of CAMKII or ATG7 was performed prior to AP induction. AP-related necrotic injury was positively regulated by the incubation level of CAMKII. ATG7 positively modulated the level of CAMKII and necrosis following AP induction, indicating that there might be a connection between impaired autophagy and CAMKII-regulated necrosis in the pathogenesis of AP. microRNA (miR)-30b-5p was predicted and then verified as the upstream regulator of CAMKII mRNA in our setting of AP. Given that the level of miR-30b-5p was negatively correlated with the incubation levels of ATG7 after AP induction, a rescue experiment was performed and indicated that the miR-30b-5p mimic compromised ATG7 overexpression-induced upregulation of CAMKII-regulated necrosis after AP induction. In conclusion, our results indicate that ATG7-enhanced impaired autophagy exacerbates AP by promoting regulated necrosis via the miR-30b-5p/CAMKII pathway.
Highlights
Because the exact underlying mechanism is still far from known and no specific therapy has yet been developed, acute pancreatitis (AP) remains a clinical challenge with considerable morbidity and mortality [1]
AP-related necrotic injury was positively regulated by the incubation level of calmodulindependent protein kinase II (CAMKII) The pathomorphological alterations of pancreatic tissues that were subjected to sham, AP, AP + Lv-CAMKII or AP + Lv-sh-CAMKII were observed by H&E staining
Necrosis was more severe in AP + Lv-CAMKII group and conclude that ATG7 positively modulated the level of CAMKII
Summary
Because the exact underlying mechanism is still far from known and no specific therapy has yet been developed, acute pancreatitis (AP) remains a clinical challenge with considerable morbidity and mortality [1]. Increasing evidence has suggested that there might be a series of signaling pathways involved in the regulation of emerging programmed cell death named regulated necrosis [2–4]. Regulated necrosis is defined as a genetically controlled cell death process that eventually results in cellular leakage, and it is morphologically characterized by cytoplasmic granulation, as well as organelle and/or cellular swelling [3]. Regulated necrosis usually consists of necroptosis, pyroptosis, parthanatos, ferroptosis and others. Among these regulated programs, only necroptosis has been relatively well elucidated by the canonical receptorinteracting protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein pathway. Our results suggested that the inhibition of RIPK1dependent regulated necrosis provided protection against AP via the RIPK1/NF-κB/aquaporin (AQP) 8 pathway, indicating a new horizon for exploring the mechanism of AP and its possible targeted therapy [5]
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