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RGS2 Repression Exacerbates Airway Hyperresponsiveness and Remodeling in Asthma
Author(s) -
Jiang Haihong,
Xie Yan,
Abel Peter,
Wolff Dennis,
Toews Myron,
Panettieri Reynold,
Casale Thomas,
Tu Yaping
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.775.10
Subject(s) - rgs2 , medicine , asthma , immunology , single nucleotide polymorphism , bronchial hyperresponsiveness , fibrosis , knockout mouse , receptor , biology , lung , gene , respiratory disease , g protein , genetics , genotype , gtpase activating protein
We recently reported that RGS2, a modulator of G q protein‐coupled receptors, is a key regulator of airway hyperresponsiveness (AHR), the hallmark of asthma. RGS2 protein levels in airway cells were significantly lower in asthmatics compared to non‐asthmatics. Interestingly, significant differences were found in the distribution of two RGS2 gene promoter single‐nucleotide polymorphisms (SNPs) (A638G, rs2746071 and C395G, rs2746072) between asthmatics and non‐asthmatics. These SNPs are associated with each other and have a higher prevalence in asthmatics (65%) than non‐asthmatics (35%). Point mutations corresponding to these SNPs decrease the RGS2 promoter activity by 44%. The pathological importance of RGS2 repression was investigated in an acute interleukin‐13 (IL‐13) mouse model of asthma. Intranasal administration of IL‐13 in mice decreased RGS2 expression in lungs by 50% and caused AHR. Although RGS2 knockout (KO) mice exhibit spontaneous AHR, IL‐13 exposure further increased AHR in these mice. Loss of RGS2 also significantly enhanced IL‐13‐induced mouse airway remodeling including peribronchial smooth muscle thickening and fibrosis. Thus, both genetic variations and increased inflammatory cytokines can lead to RGS2 repression, which exacerbates AHR and airway remodeling in asthma (American Asthma Foundation Early Excellence Award, GlaxoSmithKline Fund ADV115426 and NIH R01 HL116849 and HL097796).