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

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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) , Sang, Xiongbo, Zou, Sailan, Liu, Tingting, Mukherjee, Rajarshi ORCID: 0000-0003-0982-7883, Criddle, David N ORCID: 0000-0003-2952-8450, Zheng, Xiaofeng, Xia, Qing, Berggren, Per-Olof, Huang, Wendong, Sutton, Robert ORCID: 0000-0001-6600-562X, Tian, Yan, Huang, Wei and Fu, Xianghui (2022) A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis MOLECULAR THERAPY, 30 (4). pp. 1754-1774. ISSN 1525-0016, 1525-0024

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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 Ca²⁺ ([Ca²⁺]<inf>i</inf>) overload; however, the underlying mechanisms in Ca²⁺ overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated Ca²⁺ entry (SOCE) channel expression, Ca²⁺ 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 [Ca²⁺]<inf>i</inf> in PACs. MiR-26a deficiency increases SOCE channel expression and [Ca²⁺]<inf>i</inf> 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 [Ca²⁺]<inf>i</inf> 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 Ca²⁺ 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 & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	20 May 2022 10:16
Last Modified:	23 May 2026 06:35
DOI:	10.1016/j.ymthe.2022.01.033
Open Access URL:	https://doi.org/10.1016/j.ymthe.2022.01.033
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3155199
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