A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis

Du, Wenya, Liu, Geng, Shi, Na, Tang, Dongmei, Ferdek, Pawel E, Jakubowska, Monika A, Liu, Shiyu, Zhu, Xinyue, Zhang, Jiayu, Yao, Linbo
et al (show 13 more authors) (2022) A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis. MOLECULAR THERAPY, 30 (4). pp. 1754-1774.

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Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on translation, triggered by cytosolic Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>i</sub>) overload; however, the underlying mechanisms in Ca<sup>2+</sup> overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated Ca<sup>2+</sup> entry (SOCE) channel expression, Ca<sup>2+</sup> overload, and AP. We find that major SOCE channels are post-transcriptionally induced in PACs during AP, whereas miR-26a expression is reduced in experimental and human AP and correlated with AP severity. Mechanistically, miR-26a simultaneously targets Trpc3 and Trpc6 SOCE channels and attenuates physiological oscillations and pathological elevations of [Ca<sup>2+</sup>]<sub>i</sub> in PACs. MiR-26a deficiency increases SOCE channel expression and [Ca<sup>2+</sup>]<sub>i</sub> overload, and significantly exacerbates AP. Conversely, global or PAC-specific overexpression of miR-26a in mice ameliorates pancreatic edema, neutrophil infiltration, acinar necrosis, and systemic inflammation, accompanied with remarkable improvements on pathological determinants related with [Ca<sup>2+</sup>]<sub>i</sub> overload. Moreover, pancreatic or systemic administration of an miR-26a mimic to mice significantly alleviates experimental AP. These findings reveal a previously unknown mechanism underlying AP pathogenesis, establish a critical role for miR-26a in Ca<sup>2+</sup> signaling in the exocrine pancreas, and identify a potential target for the treatment of AP.

Item Type: Article
Uncontrolled Keywords: Animals, Humans, Mice, Pancreatitis, Acute Disease, Calcium, MicroRNAs, Calcium Signaling, Acinar Cells
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 20 May 2022 10:16
Last Modified: 18 Jan 2023 21:01
DOI: 10.1016/j.ymthe.2022.01.033
Open Access URL: https://doi.org/10.1016/j.ymthe.2022.01.033
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3155199