1. Hypercapnia increases airway smooth muscle contractility via caspase-7-mediated miR-133a-RhoA signaling.
- Author
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Shigemura M, Lecuona E, Angulo M, Homma T, Rodríguez DA, Gonzalez-Gonzalez FJ, Welch LC, Amarelle L, Kim SJ, Kaminski N, Budinger GRS, Solway J, and Sznajder JI
- Subjects
- Acetylcholine pharmacology, Aged, Aged, 80 and over, Airway Resistance, Animals, Calcium metabolism, Calpain metabolism, Carbon Dioxide, Chronic Disease, Down-Regulation drug effects, Enzyme Activation drug effects, Female, Humans, Hypercapnia genetics, MEF2 Transcription Factors metabolism, Male, Mice, Inbred C57BL, MicroRNAs genetics, MicroRNAs metabolism, Middle Aged, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle metabolism, Pulmonary Disease, Chronic Obstructive pathology, Pulmonary Disease, Chronic Obstructive physiopathology, Caspase 7 metabolism, Hypercapnia metabolism, Hypercapnia physiopathology, Muscle Contraction, Muscle, Smooth physiopathology, Signal Transduction, rhoA GTP-Binding Protein metabolism
- Abstract
The elevation of carbon dioxide (CO
2 ) 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., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2018
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