Abstract P3198: Spermidine Ameliorates Aortic Valve Degenerations By Improving Mitochondrial Biogenesis

Abstract

Aortic stenosis is the most common heart valve disease in the elderly, and aging is a leading factor. However, there is no medical treatment yet except for an operation. We investigated that mitochondrial function deteriorated in isolated human aortic valve interstitial cells (hAVICs) from the patients who had aortic stenosis (Figure A, B). We examined the therapeutic effect of spermidine (SPD) which is known to enhance mitochondrial function in the treatment of diseased hAVICs. As a result, we showed the expression of fibrosis, inflammation, and calcification markers decreased after the SPD treatment. Using the LDLR knockout mice model fed a high-fat diet, we found that the mitochondrial function in mouse AVICs improved after the SPD treatment, and the thickening, inflammation, and calcification of aortic valve leaflets significantly decreased in the SPD-fed mice (Figure C, D). Ingenuity pathway analysis from proteomic data in this animal model suggested the IRS2-AKT-TP53-SIRT1-DNMT1 pathway as a treatment mechanism and we could confirm that TP53, SIRT1, and PPARG increased while IRS2, AKT and DNMT1 were inhibited by the treatment of SPD in ex-vivo and in vitro experiments. In addition, we found that 5-azacytidine, as a DNMT1 inhibitor, induces the mitochondrial biogenesis-related genes by lowering mtDNA hypermethylation in hAVICs. In conclusion, spermidine ameliorates the mitochondrial function through the IRS-AKT-TP53-SIRT1-DNMT1 pathway in AVICs and the inhibition of DNMT1 and mtDNA hypermethylation improves mitochondrial biogenesis which can be a treatment mechanism for aortic stenosis.