Increased TGFβ1 and SMAD3 Contribute to Age-Related Aortic Valve Calcification.

Aims: Calcific aortic valve disease (CAVD) is a progressive heart disease that is particularly prevalent in elderly patients. The current treatment of CAVD is surgical valve replacement, but this is not a permanent solution, and it is very challenging for elderly patients. Thus, a pharmacological intervention for CAVD may be beneficial. In this study, we intended to rescue aortic valve (AV) calcification through inhibition of TGFβ1 and SMAD3 signaling pathways.

Methods And Results: The gene, which was discovered as an aging-suppressor gene, has been observed to play a crucial role in AV calcification. The knockout ( ) mice have shorter life span (8-12 weeks) and develop severe AV calcification. Here, we showed that increased TGFβ1 and TGFβ-dependent SMAD3 signaling were associated with AV calcification in mice. Next, we generated - and -haploinsufficient mice to determine the contribution of TGFβ1 and SMAD3 to the AV calcification in mice. The histological and morphometric evaluation suggested a significant reduction of AV calcification in ; mice compared to mice. heterozygous deletion was observed to be more potent in reducing AV calcification in mice compared to the ; mice. We observed significant inhibition of , , , , and mRNA expression in ; and ; mice compared to mice. Western blot analysis confirmed that the inhibition of TGFβ canonical and non-canonical signaling pathways were associated with the rescue of AV calcification of both ; and ; mice.

Conclusion: Overall, inhibition of the TGFβ1-dependent SMAD3 signaling pathway significantly blocks the development of AV calcification in mice. This information is useful in understanding the signaling mechanisms involved in CAVD.