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, Seokjo Kim, Naftali Kaminski, GR Scott Budinger, Julian Solway, Jacob I Sznajder*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

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

Fingerprint

Caspase 7
Hypercapnia
MicroRNAs
Smooth Muscle
Chronic Obstructive Pulmonary Disease
Smooth Muscle Myocytes
Airway Resistance
rhoA GTP-Binding Protein
Myosin Light Chains
Calpain
Calcium Signaling
Muscle Contraction
Carbon Dioxide
Lung Diseases
Transfection
Disease Progression
Up-Regulation
Down-Regulation
Phosphorylation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shigemura, Masahiko ; Lecuona, Emilia ; Angulo, Martín ; Homma, Tetsuya ; Rodríguez, Diego A. ; Gonzalez-Gonzalez, Francisco J. ; Welch, Lynn C. ; Amarelle, Luciano ; Kim, Seokjo ; Kaminski, Naftali ; Budinger, GR Scott ; Solway, Julian ; Sznajder, Jacob I. / Hypercapnia increases airway smooth muscle contractility via caspase-7-mediated miR-133a-RhoA signaling. In: Science translational medicine. 2018 ; Vol. 10, No. 457.
@article{4d5a61995eef4f40bfe6e727471495e6,
title = "Hypercapnia increases airway smooth muscle contractility via caspase-7-mediated miR-133a-RhoA signaling",
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.",
author = "Masahiko Shigemura and Emilia Lecuona and Mart{\'i}n Angulo and Tetsuya Homma and Rodr{\'i}guez, {Diego A.} and Gonzalez-Gonzalez, {Francisco J.} and Welch, {Lynn C.} and Luciano Amarelle and Seokjo Kim and Naftali Kaminski and Budinger, {GR Scott} and Julian Solway and Sznajder, {Jacob I}",
year = "2018",
month = "9",
day = "5",
doi = "10.1126/scitranslmed.aat1662",
language = "English (US)",
volume = "10",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "457",

}

Hypercapnia increases airway smooth muscle contractility via caspase-7-mediated miR-133a-RhoA signaling. / Shigemura, Masahiko; Lecuona, Emilia; Angulo, Martín; Homma, Tetsuya; Rodríguez, Diego A.; Gonzalez-Gonzalez, Francisco J.; Welch, Lynn C.; Amarelle, Luciano; Kim, Seokjo; Kaminski, Naftali; Budinger, GR Scott; Solway, Julian; Sznajder, Jacob I.

In: Science translational medicine, Vol. 10, No. 457, aat1662, 05.09.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hypercapnia increases airway smooth muscle contractility via caspase-7-mediated miR-133a-RhoA signaling

AU - Shigemura, Masahiko

AU - Lecuona, Emilia

AU - Angulo, Martín

AU - Homma, Tetsuya

AU - Rodríguez, Diego A.

AU - Gonzalez-Gonzalez, Francisco J.

AU - Welch, Lynn C.

AU - Amarelle, Luciano

AU - Kim, Seokjo

AU - Kaminski, Naftali

AU - Budinger, GR Scott

AU - Solway, Julian

AU - Sznajder, Jacob I

PY - 2018/9/5

Y1 - 2018/9/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85052807103&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052807103&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aat1662

DO - 10.1126/scitranslmed.aat1662

M3 - Article

VL - 10

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 457

M1 - aat1662

ER -