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首页> 外文期刊>Journal of atherosclerosis and thrombosis. >Effect of Sulfonylurea Agents on Reverse Cholesterol Transport in Vitro and Vivo
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Effect of Sulfonylurea Agents on Reverse Cholesterol Transport in Vitro and Vivo

机译：磺酰脲类药物对体内和体外胆固醇反向转运的影响

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Aim: Reverse cholesterol transport (RCT) is a critical mechanism for the anti-atherogenic property of HDL. The inhibitory effect of the sulfonylurea agent (SUA) glibenclamide on ATP binding-cassette transporter (ABC) A1 may decrease HDL function but it remains unclear whether it attenuates RCT in vivo . We therefore investigated how the SUAs glibenclamide and glimepiride affected the functionality of ABCA1/ABCG1 and scavenger receptor class B type I (SR-BI) expression in macrophages in vitro and overall RCT in vivo . Methods: RAW264.7, HEK293 and BHK-21 cells were used for in vitro studies. To investigate RCT in vivo , 3H-cholesterol-labeled and acetyl LDL-loaded RAW264.7 cells were injected into mice. Results: High dose (500μM) of glibenclamide inhibited ABCA1 function and apolipoprotein A-I (apoA-I)-mediated cholesterol efflux, and attenuated ABCA1 expression. Although glimepiride maintained apoA-I-mediated cholesterol efflux from RAW264.7 cells, like glibenclamide, it inhibited ABCA1-mediated cholesterol efflux from transfected HEK293 cells. Similarly, the SUAs inhibited SR-BI-mediated cholesterol efflux from transfected BHK-21 cells. High doses of SUAs increased ABCG1 expression in RAW264.7 cells, promoting HDL-mediated cholesterol efflux in an ABCG1-independent manner. Low doses (0.1-100 μM) of SUAs did not affect cholesterol efflux from macrophages despite dose-dependent increases in ABCA1/G1 expression. Furthermore, they did not change RCT or plasma lipid levels in mice. Conclusion: High doses of SUAs inhibited the functionality of ABCA1/SR-BI, but not ABCG1. At lower doses, they had no unfavorable effects on cholesterol efflux or overall RCT in vivo . These results indicate that SUAs do not have adverse effects on atherosclerosis contrary to previous findings for glibenclamide.
机译：目的：胆固醇逆向转运（RCT）是HDL抗动脉粥样硬化特性的关键机制。磺酰脲类药物（SUA）格列本脲对ATP结合盒式转运蛋白（ABC）A1的抑制作用可能会降低HDL功能，但尚不清楚它是否在体内减弱RCT。因此，我们研究了SUA格列本脲和格列美脲如何影响ABCA1 / ABCG1的功能以及巨噬细胞在体外和体内总体RCT中的I类清道夫受体B型（SR-BI）表达。方法：使用RAW264.7，HEK293和BHK-21细胞进行体外研究。为了研究体内RCT，将3H-胆固醇标记的和加载乙酰基LDL的RAW264.7细胞注入小鼠体内。结果：大剂量（500μM）的格列本脲抑制ABCA1功能和载脂蛋白A-I（apoA-I）介导的胆固醇外排，并减弱ABCA1表达。尽管格列美脲与格列本脲一样维持了RAW264.7细胞从apoA-I介导的胆固醇流出，但它抑制了ABCA1介导的从转染的HEK293细胞中胆固醇流出。同样，SUA抑制了SR-BI介导的胆固醇从转染的BHK-21细胞中流出。高剂量的SUA可以增加RAW264.7细胞中ABCG1的表达，并以独立于ABCG1的方式促进HDL介导的胆固醇外流。尽管ABCA1 / G1表达呈剂量依赖性增加，低剂量（0.1-100μM）的SUA不会影响巨噬细胞的胆固醇流出。此外，它们没有改变小鼠的RCT或血浆脂质水平。结论：大剂量SUA抑制ABCA1 / SR-BI的功能，但不抑制ABCG1。在较低剂量下，它们对体内的胆固醇流出或总体RCT没有不利影响。这些结果表明，SUA对动脉粥样硬化没有不利影响，这与以前对格列本脲的发现相反。

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