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Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis.

ABSTRACT: Mirabegron (Myrbetriq) is a ?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 ?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 development. In apolipoprotein E^-/- (ApoE ^-/-) and low-density lipoprotein (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.

SUBMITTER: Sui W

PROVIDER: S-EPMC6561204 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis.

Sui Wenhai W Li Hongshi H Yang Yunlong Y Jing Xu X Xue Fei F Cheng Jing J Dong Mei M Zhang Meng M Pan Huazheng H Chen Yuguo Y Zhang Yunjian Y Zhou Qingjun Q Shi Weiyun W Wang Xinsheng X Zhang Han H Zhang Cheng C Zhang Yun Y Cao Yihai Y

Proceedings of the National Academy of Sciences of the United States of America 20190513 22

Mirabegron (Myrbetriq) is a β3-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 β3-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 ...[more]

PMID: 31085638

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Project description:AimsBrown fat activation accelerates the uptake of cholesterol-enriched remnants by the liver and thereby lowers plasma cholesterol, consequently protecting against atherosclerosis development. Hepatic cholesterol is then converted into bile acids (BAs) that are secreted into the intestine and largely maintained within the enterohepatic circulation. We now aimed to evaluate the effects of prolonged brown fat activation combined with inhibition of intestinal BA reabsorption on plasma cholesterol metabolism and atherosclerosis development.Methods and resultsAPOE*3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective β3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged β3-AR agonism reduced faecal BA excretion (-31%), while markedly increasing plasma levels of total BAs (+258%), cholic acid-derived BAs (+295%), and chenodeoxycholic acid-derived BAs (+217%), and decreasing the expression of hepatic genes involved in BA production. In subsequent experiments, mice were additionally treated with the BA sequestrant Colesevelam to inhibit BA reabsorption. Concomitant intestinal BA sequestration increased faecal BA excretion, normalized plasma BA levels, and reduced hepatic cholesterol. Moreover, concomitant BA sequestration further reduced plasma total cholesterol (-49%) and non-high-density lipoprotein cholesterol (-56%), tended to further attenuate atherosclerotic lesion area (-54%). Concomitant BA sequestration further increased the proportion of lesion-free valves (+34%) and decreased the relative macrophage area within the lesion (-26%), thereby further increasing the plaque stability index (+44%).ConclusionBA sequestration prevents the marked accumulation of plasma BAs as induced by prolonged brown fat activation, thereby further improving cholesterol metabolism and reducing atherosclerosis development. These data suggest that combining brown fat activation with BA sequestration is a promising new therapeutic strategy to reduce hyperlipidaemia and cardiovascular diseases.

Dataset Information

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis.

Publications

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis.

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