Antiatherogenic and Cardioprotective Effects of a Xanthine Derivative KMUP‐1 in ApoE Knockout Mice

It is essential to manage cardiovascular disease related to atherosclerosis through understanding its disease progression mechanism. The effects of the xanthine derivative KMUP-1 on alleviating atherosclerosis and cardiac remodeling, as well as its underlying mechanisms, were examined. In this study, atherosclerosis and cardiac damage were induced in ApoE knockout (KO) mice by feeding them a high-fat diet (HFD) for 12 weeks. The co- and posttreatment of KMUP-1 was evaluated. Our results showed that KMUP-1 treatment significantly reduced body weight gain in HFD-induced mice. The Oil Red O and hematoxylin-eosin staining showed that KMUP-1 reduced the aortic plaque area, intima-media thickness, and intima-lumen thickness. KMUP-1 reduced inflammatory cytokines IL-1<i>β</i>, TNF-<i>α</i>, IL-6, and MCP-1 in the serum of mice through an ELISA assay. Moreover, echocardiography evaluation indicated that KMUP-1 attenuated left ventricular cardiac hypertrophy and restored cardiac function. Further, KMUP-1 treatment suppressed proapoptotic protein Bax and reversed Bcl-2 level by promoting autophagy-related Gene 7 and autophagosome marker LC3-II activation in the vascular through immunofluorescence and western blotting assay. KMUP-1 improved the serum lipidomic profile. Both co- and posttreatment of KMUP-1 stimulated autophagy and reduced inflammation and apoptosis, against atherosclerosis and cardiac remodeling in an ApoE-KO mouse model. It suggests its potential as a therapeutic agent for cardiovascular diseases.