Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness

Yan Xie, Haihong Jiang, Hoai Nguyen, Shuping Jia, Abdo Berro, Reynold A. Panettieri, Dennis W. Wolff, Peter W. Abel, Thomas B. Casale, Yaping Tu

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Background: Drugs targeting individual G protein-coupled receptors are used as asthma therapies, but this strategy is limited because of G protein-coupled receptor signal redundancy. Regulator of G protein signaling 2 (RGS2), an intracellular selective inhibitor of multiple bronchoconstrictor receptors, may play a central role in the pathophysiology and treatment of asthma. Objective: We defined functions and mechanisms of RGS2 in regulating airway hyperresponsiveness (AHR), the pathophysiologic hallmark of asthma. Methods: Real-time PCR and Western blot were used to determine changes in RGS2 expression in ovalbuminsensitized/- challenged mice. We also used immunohistochemistry and real-time PCR to compare RGS2 expression between human asthmatic and control subjects. The AHR of RGS2 knockout mice was assessed by using invasive tracheostomy and unrestrained plethysmography. Effects of loss of RGS2 on mouse airway smooth muscle (ASM) remodeling, contraction, intracellular Ca 2+, and mitogenic signaling were determined in vivo and in vitro. Results: RGS2 was highly expressed in human and murine bronchial epithelium and ASM and was markedly downregulated in lungs of ovalbumin-sensitized/-challenged mice. Lung tissues and blood monocytes from asthma patients expressed significantly lower RGS2 protein (lung) and mRNA (monocytes) than from nonasthma subjects. The extent of reduction of RGS2 on human monocytes correlated with increased AHR. RGS2 knockout caused spontaneous AHR in mice. Loss of RGS2 augmented Ca2+ mobilization and contraction of ASM cells. Loss of RGS2 also increased ASM mass and stimulated ASM cell growth via extracellular signalregulated kinase and phosphatidylinositol 3-kinase pathways. Conclusion: We identified RGS2 as a potent modulator of AHR and a potential novel therapeutic target for asthma. (J Allergy Clin Immunol 2012;130:968-76.)

Original languageEnglish (US)
Pages (from-to)968-976.e3
JournalJournal of Allergy and Clinical Immunology
Volume130
Issue number4
DOIs
StatePublished - Oct 2012

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Xie, Y., Jiang, H., Nguyen, H., Jia, S., Berro, A., Panettieri, R. A., Wolff, D. W., Abel, P. W., Casale, T. B., & Tu, Y. (2012). Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness. Journal of Allergy and Clinical Immunology, 130(4), 968-976.e3. https://doi.org/10.1016/j.jaci.2012.05.004