Hypercapnia increases airway smooth muscle contractility via caspase-7-mediated miR-133a-RhoA signaling

Masahiko Shigemura, Emilia Lecuona, Martín Angulo, Tetsuya Homma, Diego A. Rodríguez, Francisco J. Gonzalez-Gonzalez, Lynn C. Welch, Luciano Amarelle, Seok Jo Kim, Naftali Kaminski, G. R. Scott Budinger, Julian Solway, Jacob I. Sznajder*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

The elevation of carbon dioxide (CO2) in tissues and the bloodstream (hypercapnia) occurs in patients with severe lung diseases, including chronic obstructive pulmonary disease (COPD). Whereas hypercapnia has been recognized as a marker of COPD severity, a role for hypercapnia in disease pathogenesis remains unclear. We provide evidence that CO2 acts as a signaling molecule in mouse and human airway smooth muscle cells. High CO2 activated calcium-calpain signaling and consequent smooth muscle cell contraction in mouse airway smooth muscle cells. The signaling was mediated by caspase-7-induced down-regulation of the microRNA-133a (miR-133a) and consequent up-regulation of Ras homolog family member A and myosin light-chain phosphorylation. Exposure of wild-type, but not caspase-7-null, mice to hypercapnia increased airway contraction and resistance. Deletion of the Caspase-7 gene prevented hypercapnia-induced airway contractility, which was restored by lentiviral transfection of a miR-133a antagonist. In a cohort of patients with severe COPD, hypercapnic patients had higher airway resistance, which improved after correction of hypercapnia. Our data suggest a specific molecular mechanism by which the development of hypercapnia may drive COPD pathogenesis and progression.

Original languageEnglish (US)
Article numberaat1662
JournalScience translational medicine
Volume10
Issue number457
DOIs
StatePublished - Sep 5 2018

Funding

This study was supported in part by the NIH (HL-085534, HL-071643, and HL-048129).

ASJC Scopus subject areas

  • General Medicine

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