BMP‐pSmad1/5/8 Pathway Activation in Calcific Aortic Valve Disease

Calcific Aortic Valve Disease (CAVD) affects >2% of the elderly population for whom the standard of care is valve replacement surgery. Unfortunately, the pathogenic mechanisms of CAVD, which could serve as potential therapeutic targets, remain unknown. Klotho-null mice exhibit accelerated aging and aortic valve (AoV) calcification similar to human CAVD. Notably, phosphorylation of Smads1/5/8, Bone Morphogenetic Protein (BMP) pathway effectors essential for bone calcification, precedes and later localizes with calcific nodules in Klotho-null AoV. Our hypothesis is that BMP pathway activation promotes AoV calcification. Our goal is to determine the role of the BMP pathway in the pathogenesis of CAVD and to use a pharmacologic inhibitor of BMP signaling as a potential treatment for CAVD in vivo. Our current studies demonstrate that osteochondrogenic factors involved in bone and cartilage formation are significantly increased in Klotho-null AoV. In addition, BMP pathway components, including BMP2/4, Smad6 and Noggin, are significantly up-regulated in Klotho­-null AoV. Moreover, in porcine AoV interstitial cells cultured in vitro, osteogenic media treatment induces osteochondrogenic gene expression and activation of the BMP-pSmad1/5/8 pathway, as well as formation of calcific nodules. Interestingly, treatment with LDN-193189, a BMP pathway inhibitor, decreases osteochondrogenic gene induction and prevents calcific nodule formation in the presence of osteogenic media. Together these data support an active role for BMP signaling during osteochondrogenic gene induction and the development of AoV calcification. AHA Pre-doctoral Fellowship 13PRE1623006 -MVG NIH R01 HL114682 -KEY.