Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models.

Autor: Lim WW; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore.; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore., Corden B; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore.; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore.; MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, W12 0NN, UK.; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK., Ng B; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore.; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore., Vanezis K; MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, W12 0NN, UK.; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK., D'Agostino G; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore., Widjaja AA; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore., Song WH; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore., Xie C; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore., Su L; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore., Kwek XY; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore., Tee NGZ; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore., Dong J; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore., Ko NSJ; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore., Wang M; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore., Pua CJ; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore., Jamal MH; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore., Soh B; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore., Viswanathan S; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore., Schafer S; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore.; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore., Cook SA; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore. stuart.cook@duke-nus.edu.sg.; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore. stuart.cook@duke-nus.edu.sg.; MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, W12 0NN, UK. stuart.cook@duke-nus.edu.sg.; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK. stuart.cook@duke-nus.edu.sg.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2020 Oct 20; Vol. 10 (1), pp. 17853. Date of Electronic Publication: 2020 Oct 20.
DOI: 10.1038/s41598-020-74944-7
Abstrakt: Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFβ1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFβ1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.
Databáze: MEDLINE
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