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- Title
Hypercapnia increases airway smooth muscle contractility via caspase-7-mediated miR-133a-RhoA signaling.
- Authors
Shigemura, Masahiko; Lecuona, Emilia; Angulo, Martín; Homma, Tetsuya; Rodríguez, Diego A.; Gonzalez-Gonzalez, Francisco J.; Welch, Lynn C.; Amarelle, Luciano; Kim, Seok-Jo; Kaminski, Naftali; Budinger, G. R. Scott; Solway, Julian; Sznajder, Jacob I.
- Abstract
Elevated carbon dioxide (hypercapnia) activates complex signaling pathways in airway smooth muscle cells, resulting in airway constriction. Giving lungs a breath of fresh air: Severe lung disorders such as chronic obstructive pulmonary disease (COPD) are often associated with hypoventilation that can lead to hypercapnia, an elevation of carbon dioxide (CO2) in the bloodstream. Although hypercapnia has been associated with increased mortality among COPD patients, whether the increased CO2 plays a role in disease pathophysiology is unclear. Now, Shigemura and colleagues show that CO2 may act as a signaling molecule in lungs and that hypercapnia promoted smooth muscle cell contractility in mice. In COPD patients, hypercapnia was associated with increased airway resistance that was ameliorated by ventilation. The results suggest that reducing hypercapnia with noninvasive ventilation might have therapeutic effects in lung disorders. 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.
- Subjects
HYPERCAPNIA; SMOOTH muscle contraction; CASPASES; WESTERN immunoblotting; REVERSE transcriptase polymerase chain reaction; CHROMATIN; IMMUNOPRECIPITATION
- Publication
Science Translational Medicine, 2018, Vol 10, Issue 457, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aat1662