STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma.

Autor:	Johnson MT; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033., Xin P; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231., Benson JC; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231., Pathak T; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231., Walter V; Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033., Emrich SM; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033., Yoast RE; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033., Zhang X; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033., Cao G; Rutgers Institute for Translational Medicine and Science, New Brunswick, NJ 08901., Panettieri RA Jr; Rutgers Institute for Translational Medicine and Science, New Brunswick, NJ 08901., Trebak M; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033; trebakm@pitt.edu.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Jan 04; Vol. 119 (1).
DOI:	10.1073/pnas.2114557118
Abstrakt:	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 Ca 2+ 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 Ca 2+ 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 Ca 2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy. Competing Interests: The authors declare no competing interest. (Copyright © 2021 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu