Key result
Elevated osteopontin expression in calcific aortic valve stenosis alters cellular HMGB1 function, inducing its cytoplasmic translocation and secretion in endothelial and valvular interstitial cells.
Why the study?
Does osteopontin alter endothelial and valvular interstitial cell behavior and HMGB1 expression in calcific aortic valve stenosis?
Observational (n=55)
Does osteopontin alter endothelial and valvular interstitial cell behavior and HMGB1 expression in calcific aortic valve stenosis?
Osteopontin appears to regulate the progression of calcific aortic valve stenosis by altering HMGB1 function, inducing its cytoplasmic translocation and secretion in endothelial and valvular interstitial cells.
Answers are grounded in this paper and cite their sources.
Osteopontin may modulate HMGB1 in experimental CAVS; leaves open human relevance and therapeutic targeting.
OBJECTIVES: Calcific aortic valve stenosis (CAVS) is an important clinical problem predominantly affecting elderly individuals. Studies suggest that the progression of CAVS is actively regulated with valve endothelial injury leading to inflammation, fibrosis and calcification. The aim of this study was to delineate the possible regulatory role of osteopontin (OPN) on high-mobility group box 1 (HMGB1) function and the associated inflammatory and fibrotic response in CAVS. METHODS: Aortic valve leaflets were collected from CAVS patients undergoing aortic valve replacement (n = 40), and control aortic valve leaflets were obtained from heart transplant recipients (n = 15). Valves and plasma were analysed by quantitative real-time polymerase chain reaction (PCR), immunohistochemical staining and Western blot. Recombinant OPN or neutralizing OPN antibody was added to cultured endothelial and valvular interstitial cells (VICs), and cell proliferation scores and HMGB1 expression were assessed. RESULTS: CAVS valves had a decreased total percentage of VICs but increased numbers of infiltrating macrophages relative to control valves. RT-PCR studies showed higher expression of OPN, the inflammatory cytokine tumour necrosis factor-alpha as well as markers of fibrosis, tissue inhibitor of matrix metalloproteinase 1 and matrix metalloproteinase 2 in CAVS valves. Elevated expression of OPN was also observed in plasma of CAVS patients compared with controls. HMGB1 was detected in the secretory granules of cultured valve endothelial and VICs derived from CAVS valves. The addition of exogenous OPN inhibited the proliferation of cultured endothelial and VICs from CAVS valves and was associated with the extracellular expression of HMGB1, whereas neutralizing OPN had the opposite effect. CONCLUSIONS: We conclude that altered OPN expression in CAVS affects cellular HMGB1 function inducing cytoplasmic translocation and secretion of HMGB1 in endothelial cells and VICs, thus indicating a regulatory role for OPN in the progression of CAVS through alteration of HMGB1 function.
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Passmore et al. (2015) conducted an observational in Calcific aortic valve stenosis (n=55). Calcific aortic valve stenosis (elevated osteopontin expression) vs. Control aortic valve leaflets from heart transplant recipients was evaluated on Osteopontin and HMGB1 expression, and cellular proliferation. Elevated osteopontin expression in calcific aortic valve stenosis alters cellular HMGB1 function, inducing its cytoplasmic translocation and secretion in endothelial and valvular interstitial cells.
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