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.
Abstract
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 |
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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 |