Activation of the Interleukin-33/ST2 Pathway Exerts Deleterious Effects in Myxomatous Mitral Valve Disease |
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Authors: | Amaia Garcia-Pena Jaime Ibarrola Adela Navarro Alba Sadaba Carolina Tiraplegui Mattie Garaikoetxea Vanessa Arrieta Lara Matilla Amaya Fernndez-Celis Rafael Sadaba Virginia Alvarez Alicia Gainza Eva Jover Natalia Lpez-Andrs |
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Affiliation: | Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA. Irunlarrea 3, 31008 Pamplona, Spain; (A.G.-P.); (J.I.); (A.N.); (A.S.); (C.T.); (M.G.); (V.A.); (L.M.); (A.F.-C.); (R.S.); (V.A.); (A.G.); (E.J.) |
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Abstract: | Mitral valve disease (MVD) is a frequent cause of heart failure and death worldwide, but its etiopathogenesis is not fully understood. Interleukin (IL)-33 regulates inflammation and thrombosis in the vascular endothelium and may play a role in the atherosclerotic process, but its role in mitral valve has not been investigated. We aim to explore IL-33 as a possible inductor of myxomatous degeneration in human mitral valves. We enrolled 103 patients suffering from severe mitral regurgitation due to myxomatous degeneration undergoing mitral valve replacement. Immunohistochemistry of the resected leaflets showed IL-33 and ST2 expression in both valve interstitial cells (VICs) and valve endothelial cells (VECs). Positive correlations were found between the levels of IL-33 and molecules implicated in the development of myxomatous MVD, such as proteoglycans, extracellular matrix remodeling enzymes (matrix metalloproteinases and their tissue inhibitors), inflammatory and fibrotic markers. Stimulation of single cell cultures of VICs and VECs with recombinant human IL-33 induced the expression of activated VIC markers, endothelial–mesenchymal transition of VECs, proteoglycan synthesis, inflammatory molecules and extracellular matrix turnover. Our findings suggest that the IL-33/ST2 system may be involved in the development of myxomatous MVD by enhancing extracellular matrix remodeling. |
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Keywords: | interleukin-33 ST2 mitral valve myxomatous valve endothelial cells valve interstitial cells |
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