Bone Morphogenic Protein Inhibition Attenuates Bicuspid Aortic Valve Flow-Mediated Remodeling and Inflammation in Vitro
Samantha K. Atkins1, Johana Barrientos2, Philippe Sucosky2.
1University of Notre Dame, Notre Dame, IN, USA, 2Wright State University, Dayton, OH, USA.
OBJECTIVE: Bicuspid aortic valve (BAV) patients present a higher risk for developing calcific aortic valve disease (CAVD) than normal tricuspid aortic valve (TAV) patients, and the disease typically develops more rapidly and aggressively. CAVD results from changes in valvular remodeling, inflammation and cytokine signaling, which are presumed to be orchestrated in part by the bone morphogenic protein (BMP) pathway. The objective of this study was to investigate the effects of BMP inhibition on flow-mediated precursor events to CAVD in the fused BAV (F-BAV) leaflet.
METHODS: The native wall shear stress (WSS) environments on the ventricularis and fibrosa of the F-BAV leaflet were obtained from flow simulations of a BAV with left-right-coronary cusp fusion. Six tissue specimens isolated from normal porcine aortic valves were exposed to side-specific WSS conditions for 48 h using normal culture medium and medium supplemented with the BMP antagonist noggin. Inflammation, remodeling and cytokine expression were assessed through immunostaining and immunoblotting.
RESULTS: In the absence of noggin, F-BAV WSS caused significant increases in MMP-9, BMP-4 and VCAM-1 expression (2.8-, 5.0- and 124.8-fold increase, respectively, vs. fresh; p<0.05; Figure 1). Noggin supplementation significantly reduced MMP-2, MMP-9 and BMP-4 expression relative to both the fresh controls (15.6-, 2.1-, and 8.4-fold decrease, respectively; p<0.05) and conditioned tissue in normal medium (5.2-, 5.9- and 42.4-fold decrease, respectively; p<0.05), and VCAM-1 expression relative to conditioned tissue in normal medium (283.5-fold decrease; p<0.05).
CONCLUSIONS: BMP-4 is a key player in BAV flow-mediated disease. Noggin treatment on aortic valve tissue subjected to F-BAV WSS significantly reduced BMP-4 expression and attenuated the remodeling and inflammatory responses by lowering MMP-2/-9 and VCAM-1 significantly. The BMP pathway may serve as a potential therapeutic target for BAV patients to delay or prevent CAVD.
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