CaMK II Inhibition Attenuates ROS Dependent Necroptosis in Acinar Cells and Protects against Acute Pancreatitis in Mice

Abstract

As a calcium-regulated protein, CaMK II is closely related to cell death, and it participates in the development of pathological processes such as reperfusion injury, myocardial infarction, and oligodendrocyte death. The function of CaMK II activation in acute pancreatitis (AP) remains unclear. In our study, we confirmed that the expression of p-CaMK II was increased significantly and consistently in injured pancreatic tissues after caerulein-induced AP. Then, we found that KN93, an inhibitor of CaMK II, could mitigate the histopathological manifestations in pancreatic tissues, reduce serum levels of enzymology, and decrease oxidative stress products. Accordingly, we elucidated the effect of KN93 in vitro and found that KN93 had a protective effect on the pancreatic acinar cell necroptosis pathway by inhibiting the production of ROS and decreasing the expression of RIP3 and p-MLKL. In addition, we identified the protective effect of KN93 on AP through another mouse model induced by pancreatic duct ligation (PDL). Together, these data demonstrated that CaMK II participates in the development of AP and that inhibiting CaMK II activation could protect against AP by reducing acinar cell necroptosis, which may provide a new idea target for the prevention and treatment of AP in the clinic.

Triptolide Suppresses NF-κB-Mediated Inflammatory Responses and Activates Expression of Nrf2-Mediated Antioxidant Genes to Alleviate Caerulein-Induced Acute Pancreatitis

“…Fresh pancreas samples were fixed in 4% paraformaldehyde, embedded in paraffin for hematoxylin and eosin staining (H&E) and examined by light microscopy (400×). Two investigators who were blinded to the experimental treatment scored the degree of tissue injury; the scoring standards were described previously [37].…”

Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway

“…Our results showed that consistent with the Ca 2+ chelation, the inhibition of MLKL decreased the cytosolic Ca 2+ overload, indicating that Ca 2+ influxes were partly dependent on MLKL in ZEA-treated gESCs. In addition, studies implicated that Ca 2+ influxes raised cellular ROS and mediated the mitochondrial damage, thus promoting cell necroptosis in cardiac IR injury, acute pancreatitis, and heart failure [ 20 , 39 , 40 ]. In the current study, we showed that cytosolic Ca 2+ chelation with BAPTA-AM markedly inhibited the overproduction of ROS and alleviated the mitochondrial damage in gESCs caused by ZEA treatment.…”

Understanding Necroptosis in Pancreatic Diseases

“…CaMK II is a calcium-modulating protein that is upregulated in the pancreatic acinar cells of AP mice. It has been discovered that its inhibitor, KN93, protected against AP in mice by reducing oxidative stress products, reducing the expression levels of the RIPK3 and p-MLKL pathways and preventing necroptosis [ 103 ]. Some studies have evinced that inhibiting Hif-1α also alleviates AP by reducing the production of ROS and regulating the necroptosis signaling pathway [ 104 ].…”