Abstract Vascular calcification is a common pathological feature in atherosclerosis, diabetes, chronic kidney disease and aging, and is associated with increased incidence of cardiovascular events and all-cause mortality. However, effective treatments for vascular calcification remain lacking. Ursolic acid, a naturally occurring compound abundantly found in apple peels and known for its potent anti-inflammatory properties, has not been previously explored in vascular calcification. In the present study, ursolic acid (UA) inhibited osteogenic differentiation and calcification of vascular smooth muscle cells (VSMCs) in vitro, and reduced calcification in human arterial rings ex vivo. Furthermore, UA attenuated aortic calcification in CKD rats and vitamin D3-overloaded mice. Mechanistically, ursolic acid targeted 2,4-dienoyl-CoA reductase 1 (DECR1), leading to its degradation and the subsequent inhibition of the NF-κB/NLRP3 signaling pathway. This resulted in reduced expression of downstream inflammatory mediators such as cleaved Caspase-1 and IL-1β. DECR1 expression was upregulated in calcified human VSMCs, arterial rings, and CKD rat aortas. DECR1 knockdown alleviated calcification, and its overexpression aggravated calcification in VSMCs and aortic rings. This study for the first time establishes the inhibitory effects of ursolic acid on vascular calcification and identifies DECR1 as a key mediator in this process, offering new insights for potential therapeutic strategies.
Yang et al. (Thu,) studied this question.