Lanatoside C, a Novel Senolytic, Ameliorates Atherosclerosis in Mice.

Abstract

Cellular senescence, a state of irreversible cell cycle arrest, contributes to aging and age-related diseases. Senolytics targeting cellular senescence could be applied to the prevention and treatment of age-related diseases. In this study, we identified lanatoside C (Lana C) as a senolytic compound. Lana C, a cardiac glycoside used for the treatment of cardiovascular diseases, is known to inhibit the transmembrane protein sodium-potassium adenosine triphosphatase (Na⁺/K⁺-ATPase). We found that Lana C depolarized and acidified senescent human umbilical vein endothelial cells (HUVECs), making them susceptible to apoptosis. The senolytic activity of Lana C was inhibited by potassium chloride (KCl) and Z-VAD-FMK (ZVF), a widely used pan-caspase inhibitor. Additionally, Lana C significantly ameliorated the senescence burden and the formation of atherosclerotic lesions in apolipoprotein E (ApoE^-/-) or low-density lipoprotein receptor (Ldlr^-/-) knockout mice. These results suggest that Lana C could be a promising senolytic for age-related diseases.