Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 1, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2114557118
Keywords
calcium signaling; asthma; smooth muscle remodeling; CRAC channels; metabolic reprogramming
Categories
Funding
- NIH/National Heart, Lung, and Blood Institute [R35-HL150778, F30-HL147489-01A1, TL1TR002016-04, P01-HL114471]
Ask authors/readers for more resources
This study reveals the up-regulation of STIM1 in the airway smooth muscle of asthmatic mice, which is involved in the metabolic and transcriptional reprogramming process of airway remodeling and the mechanism of airway hyperresponsiveness. STIM1 regulates the activation and secretion of airway smooth muscle cells, increases mitochondrial mass, oxidative phosphorylation, and glycolytic flux, and drives the development of asthma. It is proposed as a potential target for asthma therapy.
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 mitochondria! 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available