Wenhai Sui, Hongshi Li, Yunlong Yang
May 13, 2019
Citations
1
Influential Citations
42
Citations
Quality indicators
Journal
Proceedings of the National Academy of Sciences
Abstract
Significance Mirabegron as a β3-adrenoceptor agonist is a routinely prescribed drug for treating overactive bladder syndrome. However, the effect of this drug on off-targeted tissues and organs is largely unknown. In this study, we provide mechanistic insights on mirabegron-triggered atherosclerosis in causing potential cardiovascular and cerebrovascular diseases by activation of brown fat. Given that mirabegron can induce brown fat activation in adult human subjects, these findings are clinically relevant. Moreover, genetic mutations of low-density lipoprotein receptor (LDLR) frequently occur in human populations (1 in 300 humans carries LDLR mutations). If this population of patients receive mirabegron therapy, it would be of a high risk. This important issue has not been explored in clinical studies, and warrants further investigation. 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 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.