STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma.
Proc Natl Acad Sci U S A
; 119(1)2022 01 04.
Article
in En
| MEDLINE
| ID: mdl-34949717
ABSTRACT
Airway remodeling and airway hyperresponsiveness are central drivers of asthma severity. Airway remodeling is a structural change involving the dedifferentiation of airway smooth muscle (ASM) cells from a quiescent to a proliferative and secretory phenotype. Here, we show up-regulation of the endoplasmic reticulum Ca2+ sensor stromal-interacting molecule 1 (STIM1) in ASM of asthmatic mice. STIM1 is required for metabolic and transcriptional reprogramming that supports airway remodeling, including ASM proliferation, migration, secretion of cytokines and extracellular matrix, enhanced mitochondrial mass, and increased oxidative phosphorylation and glycolytic flux. Mechanistically, STIM1-mediated Ca2+ influx is critical for the activation of nuclear factor of activated T cells 4 and subsequent interleukin-6 secretion and transcription of pro-remodeling transcription factors, growth factors, surface receptors, and asthma-associated proteins. STIM1 drives airway hyperresponsiveness in asthmatic mice through enhanced frequency and amplitude of ASM cytosolic Ca2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Respiratory Hypersensitivity
/
Asthma
/
Airway Remodeling
/
Stromal Interaction Molecule 1
/
Muscle, Smooth
Limits:
Animals
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2022
Document type:
Article