Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis
Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis
复制标题
膀胱药物米拉贝隆通过激活棕色脂肪介导的脂肪分解而加剧动脉粥样硬化
DOI：
10.1073/pnas.1901655116
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发表时间：
2019-05-28
影响因子：
11.1
通讯作者：
Cao, Yihai
中科院分区：
文献类型：
--
作者：
Sui, Wenhai;Li, Hongshi;Cao, Yihai
Mirabegron（Myrbetriq）是一种β 3-肾上腺素受体激动剂，被批准用于治疗人类患者的膀胱过度活动综合征。这种药物可以通过β 3-肾上腺素受体介导的交感神经激活来激活成年人和啮齿动物的棕色脂肪组织（BAT）。然而，美国食品和药物管理局批准的米拉贝隆对动脉粥样硬化相关心血管疾病的影响尚不清楚。在此，我们发现临床剂量的米拉贝隆诱导的BAT激活和白色脂肪组织（WAT）的布朗宁加剧了动脉粥样硬化斑块的发展。在载脂蛋白E-/-（ApoE（-/-））和低密度脂蛋白（LDL）受体（-/-）（Ldlr（-/-））小鼠中，经口给予临床相关剂量的米拉贝隆通过增加LDL-胆固醇和极LDL-胆固醇残留物的血浆水平的机制显著加速动脉粥样硬化斑块生长和不稳定性。米拉贝隆对动脉粥样硬化斑块发展的刺激依赖于产热触发的脂解。关键的产热依赖蛋白解偶联蛋白1的基因缺失完全消除了米拉贝隆诱导的动脉粥样硬化。总之，我们的研究结果表明，米拉贝隆可能会引发患有动脉粥样硬化的患者的心血管和脑血管疾病。
Mirabegron (Myrbetriq) is a beta 3-adrenoreceptor agonist approved for treating overactive bladder syndrome in human patients. This drug can activate brown adipose tissue (BAT) in adult humans and rodents through the beta 3-adrenoreceptor-mediated sympathetic activation. However, the effect of the mirabegron, approved by the US Food and Drug Administration, on atherosclerosis-related cardiovascular disease is unknown. Here, we show that the clinical dose of mirabegron-induced BAT activation and browning of white adipose tissue (WAT) exacerbate atherosclerotic plaque de- velopment. In apolipoprotein E-/- (ApoE(-/-)) and low-density lipo- protein (LDL) receptor(-/-) (Ldlr(-/-)) mice, oral administration of clinically relevant doses of mirabegron markedly accelerates atherosclerotic plaque growth and instability by a mechanism of increasing plasma levels of both LDL-cholesterol and very LDL-cholesterol remnants. Stimulation of atherosclerotic plaque development by mirabegron is dependent on thermogenesis-triggered lipolysis. Genetic deletion of the critical thermogenesis-dependent protein, uncoupling protein 1, completely abrogates the mirabegron-induced atherosclerosis. Together, our findings suggest that mirabegron may trigger cardiovascular and cerebrovascular diseases in patients who suffer from atherosclerosis.