Spermidine Enhances Mitochondrial Function and Mitigates Aortic Valve Calcification: Implications for DNA Methyltransferase-1 Activity.

Aortic stenosis (AS) is a severe heart valve disease marked by calcification, leading to heart failure. This study examined mitochondrial function in human aortic valve interstitial cells isolated from patients with AS and tested spermidine, an autophagy inducer as AS treatment. Spermidine treatment reduced fibrosis and calcification in human aortic valve interstitial cells and improved these features in spermidine-treated mice. The AKT-TP53-DNMT1-PPARG pathway was implicated, and DNA methyltransferase 1 inhibition by 5-azacytidine enhanced mitochondrial biogenesis by reducing mitochondrial DNA hypermethylation. These findings suggest that spermidine or DNA methyltransferase 1 inhibition could prevent aortic valve disease by improving mitochondrial function.