TY - JOUR
T1 - MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease
AU - Nouws, Jessica
AU - Wan, Feng
AU - Finnemore, Eric
AU - Roque, Willy
AU - Kim, So Jin
AU - Bazan, Isabel
AU - Li, Chuan Xing
AU - Magnus Skold, C.
AU - Dai, Qile
AU - Yan, Xiting
AU - Chioccioli, Maurizio
AU - Neumeister, Veronique
AU - Britto, Clemente J.
AU - Sweasy, Joann
AU - Bindra, Ranjit
AU - Wheelock, Åsa M.
AU - Gomez, Jose L.
AU - Kaminski, Naftali
AU - Lee, Patty J.
AU - Sauler, Maor
N1 - Publisher Copyright:
Copyright: © 2021, Nouws et al.
PY - 2021/1/25
Y1 - 2021/1/25
N2 - The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA that best correlated with radiographic emphysema and validated this finding in multiple cohorts. In a CS exposure mouse model, inhibition of miR-24-3p increased susceptibility to apoptosis, including alveolar type II epithelial cell apoptosis, and emphysema severity. In lung epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue, and BIM and BRCA1 expression inversely correlated with miR-24-3p. We concluded that miR-24-3p, a regulator of the cellular response to DNA damage, is decreased in COPD, and decreased miR-24-3p increases susceptibility to emphysema through increased BIM and apoptosis.
AB - The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA that best correlated with radiographic emphysema and validated this finding in multiple cohorts. In a CS exposure mouse model, inhibition of miR-24-3p increased susceptibility to apoptosis, including alveolar type II epithelial cell apoptosis, and emphysema severity. In lung epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue, and BIM and BRCA1 expression inversely correlated with miR-24-3p. We concluded that miR-24-3p, a regulator of the cellular response to DNA damage, is decreased in COPD, and decreased miR-24-3p increases susceptibility to emphysema through increased BIM and apoptosis.
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U2 - 10.1172/jci.insight.134218
DO - 10.1172/jci.insight.134218
M3 - Article
C2 - 33290275
AN - SCOPUS:85099980811
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 2
M1 - e134218
ER -