IL-33 promotes the progression of nonrheumatic aortic valve stenosis via inducing differential phenotypic transition in valvular interstitial cells

Yu-Bin He; Jiang-Hong Guo; Chong Wang; Dan Zhu; Li-Ming Lu

doi:10.1016/j.jjcc.2019.06.011

IL-33 promotes the progression of nonrheumatic aortic valve stenosis via inducing differential phenotypic transition in valvular interstitial cells

J Cardiol. 2020 Feb;75(2):124-133. doi: 10.1016/j.jjcc.2019.06.011. Epub 2019 Aug 13.

Authors

Yu-Bin He¹, Jiang-Hong Guo², Chong Wang¹, Dan Zhu³, Li-Ming Lu⁴

Affiliations

¹ Department of Cardiovascular Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
² The Rugao People's Hospital, Teaching Hospital of Nantong University, Rugao, China.
³ Department of Cardiovascular Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
⁴ Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].

PMID: 31416779
DOI: 10.1016/j.jjcc.2019.06.011

Abstract

Objective: Interleukin (IL)-33 is a mediator in the pathogenesis of several inflammatory diseases. Its receptor, ST2, is overexpressed in nonrheumatic aortic valve stenosis (NR-AS). This study compared smooth muscle α-actin (α-SMA), osteopontin (OPN), and suppression of tumorigenicity 2 (ST2) expression between specimens from fibrotic and calcific stages of NR-AS and observed the effects and mechanisms of phenotypic transition of porcine valvular interstitial cells (VICs) in the presence of IL-33.

Methods: Peripheral blood IL-1 family mRNA and protein levels in NR-AS patients and healthy adults were quantified by real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay. Immunohistochemistry and immunofluorescence were used to detect the expression and coexpression of α-SMA, OPN, and ST2 in NR-AS specimens. Porcine VICs were stimulated with IL-33, IL-33+SB203580, or IL-33+SC75741. mRNA and protein expression levels of porcine VICs were detected by RT-qPCR and western blot.

Results: The mRNA and protein levels of IL-33 and sST2 in peripheral blood of NR-AS patients were higher than those in healthy adults. Immunohistochemistry and immunofluorescence showed higher expression of α-SMA, OPN, and ST2 in the calcific stage of NR-AS than in the fibrotic stage. Coexpression of ST2/α-SMA or ST2/OPN was found only in the calcific stage. Nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) phosphorylation levels were associated with IL-33-induced porcine VIC differentiation into myofibroblasts and osteoblasts, respectively. IL-33 stimulation also promoted the coexpression of ST2/OPN or α-SMA/OPN/ST2.

Conclusion: IL-33 might be a potential biomarker for NR-AS. IL-33-induced porcine VIC differential phenotypic transition and differentiation into myofibroblasts and osteoblasts were dependent on the NF-κB and p38 MAPK signaling pathways, respectively.

Keywords: Aortic valve; Calcification; Interleukin-33; Phenotypic transition; Valvular interstitial cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Aortic Valve / cytology*
Aortic Valve Stenosis / blood*
Aortic Valve Stenosis / genetics
Aortic Valve Stenosis / metabolism
Biomarkers / blood
Biomarkers / metabolism
Cell Differentiation
Disease Progression
Female
Humans
Interleukin-1 Receptor-Like 1 Protein / genetics
Interleukin-1 Receptor-Like 1 Protein / metabolism
Interleukin-33 / blood*
Interleukin-33 / genetics
Interleukin-33 / metabolism
Male
Middle Aged
Phenotype
Swine

Substances

Biomarkers
IL1RL1 protein, human
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33