| First Author | Chakrabarti M | Year | 2022 |
| Journal | Front Cardiovasc Med | Volume | 9 |
| Pages | 770065 | PubMed ID | 35928937 |
| Mgi Jnum | J:327131 | Mgi Id | MGI:7327723 |
| Doi | 10.3389/fcvm.2022.770065 | Citation | Chakrabarti M, et al. (2022) Increased TGFbeta1 and SMAD3 Contribute to Age-Related Aortic Valve Calcification. Front Cardiovasc Med 9:770065 |
| abstractText | 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 TGFbeta1 and SMAD3 signaling pathways. Methods and Results: The klotho gene, which was discovered as an aging-suppressor gene, has been observed to play a crucial role in AV calcification. The klotho knockout (Kl (-/-)) mice have shorter life span (8-12 weeks) and develop severe AV calcification. Here, we showed that increased TGFbeta1 and TGFbeta-dependent SMAD3 signaling were associated with AV calcification in Kl (-/-) mice. Next, we generated Tgfb1- and Smad3-haploinsufficient Kl (-/-) mice to determine the contribution of TGFbeta1 and SMAD3 to the AV calcification in Kl (-/-) mice. The histological and morphometric evaluation suggested a significant reduction of AV calcification in Kl (-/-); Tgfb1 (+/-) mice compared to Kl (-/-) mice. Smad3 heterozygous deletion was observed to be more potent in reducing AV calcification in Kl (-/-) mice compared to the Kl (-/-); Tgfb1 (+/-) mice. We observed significant inhibition of Tgfb1, Pai1, Bmp2, Alk2, Spp1, and Runx2 mRNA expression in Kl (-/-); Tgfb1 (+/-) and Kl (-/-); Smad3 (+/-) mice compared to Kl (-/-) mice. Western blot analysis confirmed that the inhibition of TGFbeta canonical and non-canonical signaling pathways were associated with the rescue of AV calcification of both Kl (-/-); Tgfb1 (+/-) and Kl (-/-); Smad3 (+/-) mice. Conclusion: Overall, inhibition of the TGFbeta1-dependent SMAD3 signaling pathway significantly blocks the development of AV calcification in Kl (-/-) mice. This information is useful in understanding the signaling mechanisms involved in CAVD. |
