Mol Ther.2022 Jan 22. (IF:11.454).

A microRNA checkpoint for Ca 2+ signaling and overload in acute pancreatitis

Wenya Du  1 Geng Liu  1 Na Shi  2 Dongmei Tang  1 Pawel E Ferdek  3 Monika A Jakubowska  4 Shiyu Liu  5 Xinyue Zhu  1 Jiayu Zhang  1 Linbo Yao  5 Xiongbo Sang  1 Sailan Zou  1 Tingting Liu  5 Rajarshi Mukherjee  6 David N Criddle  7 Xiaofeng Zheng  8 Qing Xia  5 Per-Olof Berggren  9 Wendong Huang  10 Robert Sutton  11 Yan Tian  12 Wei Huang  13 Xianghui Fu  14 Affiliations


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+]i) 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+]i in PACs. MiR-26a deficiency increases SOCE channel expression and [Ca2+]i 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+]i 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.

Keywords: autophagy; endoplasmic reticulum stress; inflammation; mouse models; noncoding RNA; pancreatic acinar cell; store-operated calcium entry channels; targeted therapy; transient receptor potential canonical channels.