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

W Sui, H Li, Y Yang, X Jing, F Xue… - Proceedings of the …, 2019 - National Acad Sciences
W Sui, H Li, Y Yang, X Jing, F Xue, J Cheng, M Dong, M Zhang, H Pan, Y Chen, Y Zhang…
Proceedings of the National Academy of Sciences, 2019National Acad Sciences
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 …
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.
National Acad Sciences