Calcific Aortic Valve Disease (CAVD) affects >2% of the population over the age of 65, for whom the current standard of care is valve replacement surgery. To date, there are no pharmacologic-based therapies that prevent the progression or inhibit the development of CAVD, thus highlighting the necessity for new therapeutic approaches. Despite its clinical significance, the pathogenic mechanisms that drive the development of CAVD, and that could serve as potential therapeutic targets, remain unknown. We have recently identified Klotho-deficient mice, an established model of premature aging, as a novel model of CAVD that exhibit aortic valve calcification on the fibrosa side of the hinge region, closely mimicking human CAVD pathology. Unlike previous models, calcification occurs independent of inflammation and valve thickening in these mice, supporting a distinct mechanism of age-related calcification common in elderly patients. In bone, BMP-mediated osteogenic gene induction is essential for the process of calcification. Notably, pSmad1/5/8 activation, indicative of active BMP signaling, is observed prior to the onset of calcification and later is localized with calcific nodule formation in klotho-deficient mice with CAVD. Our hypothesis is that activation of BMP-pSmad1/5/8 signaling pathway promotes osteogenic gene induction and aortic valve mineralization in CAVD. Osteogenic factors, Runx2 and Osteopontin, are significantly increased in the aortic valves of klotho-deficient mice, suggesting an osteogenic-like mechanism of disease. Likewise, pSmad1/5/8 activation precedes osteogenic gene induction in these mice. Moreover, increased BMP2/4 ligand expression is detected prior to the onset of disease, as well as during calcific nodule formation, thus supporting an active role for the BMP-pSmad1/5/8 signaling cascade during aortic valve calcification. Our ongoing work includes BMP pathway inhibition studies to determine if this is an effective therapeutic strategy for the treatment of CAVD in the klotho-deficient mice. Altogether our data support a role for the BMP-pSmad1/5/8 signaling cascade as a critical mechanism in the initial onset and progression of aortic valve calcification in a novel mouse model of CAVD.
Wnt signaling in heart valve development and osteogenic gene induction
