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

TL;DR

This study shows that a xanthine derivative called KMUP-1 can reduce atherosclerosis and heart damage in mice, suggesting it may be a promising treatment for cardiovascular diseases.

Contribution

The study demonstrates that KMUP-1 reduces atherosclerosis and cardiac remodeling in ApoE knockout mice through autophagy stimulation and anti-inflammatory effects.

Findings

KMUP-1 reduced aortic plaque area and intima-media thickness in HFD-induced ApoE knockout mice.

KMUP-1 decreased inflammatory cytokines IL-1β, TNF-α, IL-6, and MCP-1 in the serum of mice.

KMUP-1 attenuated cardiac hypertrophy and improved cardiac function while promoting autophagy-related gene activation.

Abstract

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-1β, TNF-α, 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.

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