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

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.

The Role of Transforming Growth Factor-β Signaling in Myxomatous Mitral Valve Degeneration

“…While much is known about the cellular and molecular events of the disease in both species, the exact molecular and regulatory mechanisms are not yet elaborated, especially with regard to early disease onset and progression ( 3 – 5 , 37 ). In human MVP most studies of non-syndromic forms have been restricted to examining end-stage valves obtained at surgery ( 29 , 34 , 35 , 40 ). Information on earlier onset is restricted mainly to inherited connective tissue disorders, such as MFS, osteogenesis imperfecta, and Ehlers-Danlos syndrome, although myxomatous degeneration in those patients can appear with advanced age ( 17 ).…”

Serum Proteomic Profiles Reflect the Stages of Myxomatous Mitral Valve Disease in Dogs

“…In human medicine, compared to Gal-3 protein, soluble ST2 (sST2) was characterized as a superior marker for cardiac remodeling and cardiac fibrosis [ 26 ]. Although ST2 proved to be an unspecific marker, recent studies on myxomatous degeneration suggest that the cytokine interleukin-33/ST2 pathway may be amplifying extracellular matrix remodeling in mitral valves [ 27 ]. Unfortunately, studies investigating circulating ST2 concentrations in canine MMVD [ 17 , 28 ], including our study, have, up to now, not been successful in showing significant differences between healthy and diseased states.…”

Progress of Research into the Interleukin-1 Family in Cardiovascular Disease

“…108 Moreover, IL-33 binding to ST2 receptors activated valvular interstitial cells and promoted mesenchymal transformation of valve endothelial cells, contributing to mitral mucinous tumor degeneration. 109 IL-37 was found to be expressed in both aortic disease and mitral valve disease but with lower levels at the site of aortic stenosis. 110 Recombinant IL-37 attenuated the osteogenic response in valves by inhibiting the NF-κB and ERK1/2 signaling pathways and reducing bone morphogenetic protein-2 and alkaline phosphatase release.…”

“… 108 Moreover, IL-33 binding to ST2 receptors activated valvular interstitial cells and promoted mesenchymal transformation of valve endothelial cells, contributing to mitral mucinous tumor degeneration. 109 …”