The Xanthine Derivative KMUP-1 Attenuated the Progression of Atherosclerosis in Apolipoprotein E-Knockout Mice.

• Main Authors: Chih-Chieh Hsu, 許智傑
• Other Authors: Jwu-Lai Yeh
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/33c37n

碩士 === 高雄醫學大學 === 醫學系藥理學科碩士班 === 103 === 　　Atherosclerosis, a complex chronic inflammatory and metabolic disease, remains the leading cause of morbidity and mortality worldwide. Which is caused by the recruitment of blood monocytes, deposition of lipids, and formation of macrophage foam cells in the arterial wall. Apolipoprotein E-knockout (ApoE-KO) mice, a classic model of atherosclerosis, develop spontaneous atherosclerosis and thus have been widely used in cardiovascular research. In our previous studies, KMUP-1, a chemical synthetic xanthine-based derivative, has been shown its abilities of anti-inflammatory, anti-proliferation, and cardioprotective properties. This study aims to investigate whether KMUP-1 plays a protective role in inhibiting the progression of atherosclerosis in ApoE-KO mice. 　　For atherosclerosis studies, male ApoE-KO mice were randomly divided into four groups at the age of 8 weeks. High fat diet (HFD), prevention (KMUP-1-P) and treatment (KMUP-1-T) groups were fed with western diet containing 0.15% cholesterol and 21% fat (wt/wt) for 12 weeks. And the control (CTL) group was fed a normal chow diet for the same period. The KMUP-1-P group was administrated with KMUP-1 (5mg/kg/day) dissolved in drinking water for whole 12 weeks while the KMUP-1-T group for the last 4 weeks before sacrificing. According to our studies, KMUP-1 alleviated body and heart weight gain of ApoE-KO mice. In the echocardiography, FS% and EF% were improved in the KMUP-1-P and KMUP-1-T groups compared with the HFD group. The blood lipid profiles showed that KMUP-1 tended to decrease the level of TC, TG and LDL. However, KMUP-1 could somewhat increase the HDL level. Likewise, inflammatory cytokines IL-1?? and TNF-?? was decreased by KMUP-1. Histologically, atherosclerotic plaque with Oil-Red-O positive lesion areas were decreased in KMUP-1-given ApoE-KO mice. 　　KMUP-1 seemed to increase protein expressions of Atg7, Beclin-1, Bax and Bcl-2 in the aortic tissue of ApoE-KO. It is possible that KMUP-1 makes a protective role in the progression of atherosclerosis in ApoE-KO mice through the autophagy pathway. The results in our studies indicated that KMUP-1 may be a potential agent to restrict atherosclerosis development.