Abstract 13697: Calcific Aortic Valve Stenosis is Associated with an Alteration in HMGB1 Secretion by Endothelial Cells, Myofibroblasts and Macrophages
Calcific aortic valve stenosis (CAVS) is an important clinical problem. Studies suggest the progression of CAVS is actively regulated with endothelial injury leading to a sustained and chronic inflammatory state and fibrosis and calcification. HMGB1 has been implicated in vasculature related pathologies such as cancer, diabetes, arthritis and atherosclerosis. We hypothesised that active release of HMGB1 by inflammatory cells and/or passive release by cells resident in the valve regulates CAVS progression. Calcified leaflets were collected from patients undergoing valve replacement (n=21;median age 76; 8 female, 13 male) and controls from heart transplant recipients (n=10; median age 54; 5 female, 5 male). Immunohistochemical staining was performed on cultured endothelial and myofibroblast cells and macrophages in the valve leaflet. The gene expression levels of HMGB1, MMP2, MMP9, TIMP1, TIMP2 and TNFα were also evaluated. Pathological remodelling in CAVS was associated with atherosclerotic progression, calcification, macrophageinfiltration and collagen accumulation. HMGB1 expression was found to be associated with myofibroblasts, endothelial cells and macrophage infiltrate and area of acellular collagen and calcific accumulation in CAVS. There were increased numbers of macrophages in CAVS compared to controls (22.5 ± 3.9% vs 14.7 ± 4.3%). The total percentage of myofibroblasts decreased by 8% in CAVS versus controls. Using a Mann-Whitney test gene expression studies showed a decrease in HMGB1 (p=0.034) and increased TNFα (p=0.039) and TIMP1 (p=0.012) in CAVS with no change in MMP2 and MMP9 indicating active fibrosis. HMGB1 staining was identified in secretory lysosomes indicative of active release with no staining in controls. The results of this study show that in CAVS HMGB1 is actively released by myofibroblasts, endothelial cells and macrophages and accumulated extracellularly in the area of myofibroblast loss associated with fibrosis and calcification. Decreased HMGB1 gene expression levels reflect a lack of cell numbers in the calcified valve. In conclusion, HMGB1 is altered in CAVS and its secretion in myofibroblasts, endothelial cells and macrophages of the calcified valve is implicated in pathological remodelling.
- © 2012 by American Heart Association, Inc.