Abstract
BackgroundAortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. Here, we tested the hypothesis that side-dependent activation of bone morphogenic protein (BMP) pathway in the endothelium of the ventricularis and fibrosa is associated with human AV calcification.Methods and ResultsHuman calcified AVs obtained from AV replacement surgeries and non-calcified AVs from heart transplantations were used for immunohistochemical studies. We found SMAD-1/5/8 phosphorylation (a canonical BMP pathway) was higher in the calcified fibrosa than the non-calcified fibrosa while SMAD-2/3 phosphorylation (a canonical TGFβ pathway) did not show any difference. Interestingly, we found that BMP-2/4/6 expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both calcified and non-calcified AV cusps; however, BMP antagonists (crossvienless-2/BMPER and noggin) expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both disease states. Moreover, significant expression of inhibitory SMAD-6 expression was found only in the non-calcified ventricularis endothelium.ConclusionsSMAD-1/5/8 is preferentially activated in the calcified fibrosa endothelium of human AVs and it correlates with low expression of BMP antagonists and inhibitory SMAD6. These results suggest a dominant role of BMP antagonists in the side-dependent calcification of human AVs.
Highlights
Aortic valve (AV) disease is a major cause of cardiac deaths worldwide and is a strong risk factor for additional cardiovascular events [1,2,3]
SMAD-1/5/8 is preferentially activated in the calcified fibrosa endothelium of human AVs and it correlates with low expression of bone morphogenic protein (BMP) antagonists and inhibitory SMAD6
These results suggest a dominant role of BMP antagonists in the side-dependent calcification of human AVs
Summary
Aortic valve (AV) disease is a major cause of cardiac deaths worldwide and is a strong risk factor for additional cardiovascular events [1,2,3]. In a study looking at side-specific mRNA of the AV endothelium of porcine AVs, Simmons et al found the proinflammatory and bone growth chemokine bone morphogenic protein 4 (BMP-4) was expressed on the fibrosa endothelium, while chordin, a natural BMP antagonist, was found to be up-regulated on the ventricularis endothelium. It was reported that BMPs -2 and -4 are present in calcified regions of human AV [21] It is not known whether BMPs are activated in endothelial cells in a side-dependent manner and whether it correlates with calcification in human AVs. Aortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. We tested the hypothesis that side-dependent activation of bone morphogenic protein (BMP) pathway in the endothelium of the ventricularis and fibrosa is associated with human AV calcification
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