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