Abstract
Calcific aortic stenosis affects a large number of people 65 or older. Our previous studies found that stimulation of TLR2 or TLR4 in human aortic valve interstitial cells (AVICs) up-regulates the expression of osteogenic mediators. Identification of endogenous agents that activate TLR2 and TLR4 in AVICs could lead to pharmacological intervention of calcific aortic stenosis. While biglycan and oxLDL accumulate in diseased areas of aortic valves, their role in the development and progression of this valve disease is poorly understood. Soluble biglycan is recognized as an endogenous ligand for TLR2 and TLR4 in macrophages. We recently found that oxLDL induces bone morphogenetic protein-2 (BMP-2) expression in human coronary artery endothelial cells. This study tested the hypothesis that soluble biglycan induces the osteogenic response in human AVICs via TLR2/4 and mediates the pro-osteogenic effect of oxLDL. Methods and results: The expression and release of biglycan were greater in AVICs of stenotic valves. Stimulation of cells with biglycan (0.05-0.20 μg/ml) increased the expression of BMP-2 and alkaline phosphatase (ALP). Further, prolonged stimulation with biglycan caused accumulation of calcium deposits in AVIC culture. Silencing of TLR2, not TLR4, markedly reduced protein levels of BMP-2 and ALP following stimulation with biglycan. Co-immunoprecipitation revealed the interaction of biglycan with TLR2. Biglycan induced the phosphorylation of ERK1/2 and p38 MAPK, and inhibition of either ERK1/2 or p38 MAPK reduced biglycan-induced expression of BMP-2 and ALP. Stimulation of AVICs with oxLDL (20 and 40 μg/ml) up-regulated biglycan expression and release. Neutralization or silencing of biglycan reduced the effect of oxLDL on the expression of BMP-2 and ALP. Conclusions: Extracellular soluble biglycan induces the osteogenic response in AVICs via TLR2. The ERK1/2 and p38 MAPK pathways are involved in mediating the pro-osteogenic effect of soluble biglycan. OxLDL stimulates the synthesis and release of biglycan by AVICs, and biglycan contributes to the mechanism underlying the pro-osteogenic effect of oxLDL on AVICs. These findings provide evidence supporting a pathobiological role of soluble biglycan and oxLDL in calcific aortic stenosis.
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