Vascular calcification, a common complication of metabolic diseases such as diabetes and obesity, is closely associated with chronic inflammation and contributes to cardiovascular morbidity. The adipokine visfatin, which is secreted by visceral fat, is a proinflammatory mediator linked to metabolic dysfunction. In this study, we investigated its role in vascular calcification. A murine model was established by vitamin D injection. Serum visfatin levels were significantly elevated in patients with higher coronary artery calcification scores and in calcified mice, accompanied by increased visfatin expression in visceral fat. Adipose tissue-specific overexpression of visfatin further exacerbated vitamin D-induced vascular calcification. In cultured vascular smooth muscle cells (VSMCs), visfatin increased osteogenic differentiation under calcification conditions. Mechanistically, visfatin directly bound to TLR4 to promote osteogenic transformation of VSMCs, whereas TLR4 knockout markedly attenuated visfatin- and calcification medium-induced aortic calcification both in vivo and in vitro. Furthermore, the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin alleviated vascular calcification and reduced serum visfatin levels in mice. Mechanistically, empagliflozin suppressed p38/NF-κB activation, inhibited NF-κB nuclear translocation, and reduced NF-κB binding to the visfatin promoter, thereby decreasing visfatin expression in adipocytes. Collectively, these findings identify visfatin as a proinflammatory adipose-derived regulator of vascular calcification via TLR4 and a potential therapeutic target for vascular calcification and related cardiovascular disorders.
Zhang et al. (Wed,) studied this question.