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

Abstract

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. mirabegron | atherosclerosis | plaque instability | lipolysis | adipose tissue A therosclerosis, the thickening, hardening, and loss of elasticity of the arterial vessel wall, is the major cause of morbidity and mortality worldwide (1-4). Atherosclerotic lesions containing fatty plaques, cholesterol, and inflammatory cells are the primary causes of cardiovascular disease and stroke (5, 6). Atherosclerosis as a chronic and progressive disease usually starts with damage of the endothelial layer of an artery. Hypertension, hyperglycemia, hyperlipidemia especially hypercholesterolemia, smoking, obesity and diabetes, certain inflammatory disorders such as arthritis, infections, and drugs are the common risk factors of atherosclerotic plaque formation (7,8). Of interest, high incidences of myocardial infarction and stroke have been associated with colder ambient temperature and cold seasons (9, 10). Although the exact mechanism underlying low ambient temperature has not been elucidated, our recent findings show that cold-induced lipolysis in brown adipose tissue (BAT) and browning of white adipose tissue (WAT) may partly explain the high incidences of cardiovascular disease and stroke (11).The balance between energy deposition and dissipation is regulated by multiple factors, including the central nervous system, the endocrine system, food intake, physical exercise, pathological disease, and medications (12,13). Although WAT stores excessive energy in its lipid form, activated BAT specializes energy consumption by producing heat (14,15). Under certain conditions such as cold exposure, WAT, especially that located in the s.c. region, undergoes the brown-like transition, a process named browning WAT (16,17). Instead of stor...

Browning of White Adipose Tissue as a Therapeutic Tool in the Fight against Atherosclerosis

“…Its integrity is essential to procure anti-atherogenic effects of thermogenic AT [ 13 ]. This suggests that BAT and wBAT stimulation by cold exposure or β3-adrenoreceptor agonists may lead to the same pro-atherosclerotic impact seen in previous studies conducted in the similar mouse model [ 105 , 106 , 107 ]. Thus, the browning process is a potential and non-negligible risk factor for the 1 in 250 people with this disease [ 120 ].…”

“…However, the same cold condition was beneficial for the lipidic profile of wild-type mice and decreased atherogenesis [ 106 ]. Another recent study reported increased atherosclerosis development in Apoe −/− and Ldlr −/− mice treated with a β3-adrenoceptor agonist [ 107 ]. Both the Apoe −/− and Ldlr −/− mice showed reduced clearance of triglycerides-rich apolipoprotein remnants by the liver.…”

Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity

“…In addition, GPCRs have high medical relevance because they constitute the major target of currently available drugs (Hauser et al, 2017). Since systemic stimulation of cAMP signaling via beta2-and beta3-adrenergic receptors (beta2-and beta3-AR) is associated with significant cardiovascular side effects including hypertension and atherosclerosis (Cypess et al, 2015;Sui et al, 2019), the identification of alternative pathways is not only of biological interest, but also has translational potential.…”

Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue

“…Administration of YM-178 to mice for 4-6 weeks at similar dosage to this study (i.e. 0.8mg/kg) reduces fat mass, increases UCP1 in IWAT and glucose uptake in BAT at standard housing temperature (SHT) whilst driving atherosclerosis, through BAT lipolysis in ApoE-/- and LdlR-/- mice [32]. Here, we show YM-178 treatment in obese animals raised at thermoneutraility has no impact on thermogenesis although it does modulate specific proteins involved in cell differentiation and skeletal muscle contraction.…”