Activating Sirt1 reduces aortic valve calcification in mice and human cells

In human aortic valves and apolipoprotein E-deficient mice, researchers examined how Sirtuin 1 affects calcific aortic valve disease. The team observed that Sirt1 levels dropped in calcified human valves and cultured human aortic valve interstitial cells. Overexpressing Sirt1 in these human cells restored mitochondrial function, reduced iron accumulation, and blocked osteogenic differentiation by suppressing ferroptosis. These benefits depended on activating the Nrf2/HO-1/FTH1 signaling pathway. Blocking Nrf2 or inducing ferroptosis eliminated the protective effects. In mice fed a Western diet, the Sirt1 activator SRT2104 reduced aortic valve calcification and tissue remodeling. Silencing HO-1 or FTH1 partially reversed these improvements in the mice. Together, the findings show that Sirt1 maintains iron homeostasis and mitochondrial health to limit valve calcification.