Activation of the Interleukin-33/ST2 Pathway Exerts Deleterious Effects in Myxomatous Mitral Valve Disease.

Amaia Garcia-Pena,Alba Sadaba,Natalia López-Andrés,Jaime Ibarrola,Rafael Sadaba,Vanessa Arrieta,Alicia Gainza,Lara Matilla,Adela Navarro,Carolina Tiraplegui,Virginia Alvarez,Mattie Garaikoetxea,Amaya Fernández-Celis,Eva Jover

doi:10.3390/ijms22052310

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.

Highlights

Introduction published maps and institutional affilMitral valve disease (MVD) is the most common valvular heart condition, with an estimated prevalence of 1.8% moderate or severe MVD in the general population [1]
We have demonstrated for the first time the expression of IL-33 and ST2L in mitral valves and their colocalization with valve interstitial cells (VICs) and valve endothelial cells (VECs)
We found that the tissue levels of IL-33 correlate with the levels of molecules implicated in the development of myxomatous degeneration of the mitral valve, such as inflammatory cytokines and extracellular matrix components and matrix metalloproteinases

Summary

Introduction

Mitral valve disease (MVD) is the most common valvular heart condition, with an estimated prevalence of 1.8% moderate or severe MVD (either mitral regurgitation or stenosis) in the general population [1]. MVD is a major source of morbidity and death worldwide and a frequent cause of heart failure [2]. The etiology of MVD can be broadly divided into primary and secondary based on whether the mitral leaflets exhibit significant pathological abnormalities or not [3]. The commonest cause of primary MVD is myxomatous degeneration, most frequently mitral valve prolapse (MVP) [3,4]. The histopathology is characterized by architectural changes in the leaflets consisting of fragmentation of collagen with an increase in extracellular proteoglycans (PGs) in the spongiosa layer of the leaflet [5,6]. The main cellular components of cardiac valves are the valve endothelial cells (VECs) and valve interstitial cells (VICs), which maintain tissue homeostasis [7,8]

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