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

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.