Inflammation and calcification are common features of the aortic valve (AV) diseases, which typically require surgical replacement of the valves. While gross pathological changes and surgical treatments of the diseased valves have received much attention, the molecular mechanisms underlying AV inflammation and calcification are not well understood AV diseases preferentially occur in the aortic side (fibrosa) of the valvular leaflets, which is exposed to unstable hemodynamic conditions including oscillating shear stress (OS ), strain and bending. In contrast, the ventricular side of the leaflets, is exposed to relatively stable flow conditions, is spared. Defining the underlying molecular mechanisms is the goal of this application. Through a recent micoarray study using porcine AV endothelial cells (PAVEC) exposed to stable laminar shear (LS), we found that BMP4 expression is significantly downregulated by LS, and the fibrosa eridothelium expresses significantly higher amount of BMP4 protein than the ventricular side. Interestingly, we have also shown that BMP4 is a OS-inducible, pro-inflammatory cytokine in aortic EC (AEC). We hypothesize that exposure of AVEC to the unstable flow conditions (OS) stimulates BMP4 expression, which in turn induces inflammatory responses. The recruited inflammatory cells in the face of continued unfavorable local hemodynamic environment would then lead to clacification and valve failure. To test these hypotheses, cultured AVEC and three different Apoliprotein E-deficient mice lines (ApoE and ApoE containing endothelium-targeted BMP4 or the BMP receptor (alk3) knockout) will be used.
AIM 1 will determine the effects of shear stress on BMP expression and inflammatory responses in AVEC.
Aim 2 will define the BMP signaling pathways mediating shear-independent inflammation in AVEC.
Aim 3 will determine whether AV inflammation and calcification in ApoE-null mice can be induced by BMP4 and prevented by endothelium-targeting, include knockout of BMP4 or the BMP receptor (Alk3). Identification of BMP4 as the mechanosensitive, pro-inflammatory cytokine leading to AV inflammation and calcification may provide a potential non-surgical therapeutic avenue to treat and prevent AV diseases. ? ? ?
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