Spermidine Enhances Mitochondrial Function and Mitigates Aortic Valve Calcification
Naaleum Song, Eunhye Ji, Jeong Eun Yu, Kyoung‐Hee Choi, Dae‐Hee Kim, Jong‐Min Song, Duk‐Hyun Kang, Jae‐Kwan Song, Jiyoung Yu, Kyunggon Kim, Sahmin Lee, Elena Aïkawa
Abstract
• This study elucidates the role of mitochondrial dysfunction in AS and highlights its contribution to the pathological remodeling of the aortic valve. • Spermidine, a natural autophagy inducer, was shown to inhibit calcification-related factors and improve mitochondrial function in human aortic valve interstitial cells (hAVICs) isolated from AS patients. • The research identified the AKT-TP53-DNMT1-PPARG pathway as a key mechanism through which spermidine exerts its protective effects on the aortic valve. • Spermidine-treated mice showed reduced aortic valve pathology, supporting the potential for in vivo therapeutic application. • The study suggests that targeting mitochondrial function through DNMT1 inhibition or spermidine supplementation could be a promising strategy for preventing and treating AS. 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.