Sex-Specific Effects of the β3-Adrenergic Receptor Agonist Mirabegron in a Murine Two-Hit Heart Failure Model with Preserved Ejection Fraction

Background. In addition to its role in thermogenesis, activation of the brown adipose tissue (BAT) has been shown to produce factors (batokines) that can protect the cardiovascular system, particularly the heart, in pathological situations such as hypertension, atherosclerosis, and ischemia/reperfusion injury, BAT activation is mediated via the β3-adrenergic receptor (β3-AR), which is abundantly expressed in this tissue. In this study, we investigated whether using a specific β3-AR agonist, mirabegron, could slow the development of heart failure with preserved ejection fraction (HFpEF) in C57Bl6/J male and female mice after a metabolic-hypertensive stress (MHS).Methods. Eight-week-old mice of both sexes were divided into four groups. Control, mirabegron (Mira) (2 mg/kg/day), MHS (Angiotensin II [1.5mg/kg/day] + a high-fat diet) or MHS + mirabegron for 28 days. At the end of the protocol, all animals had an echocardiography exam, and the heart, lungs, BAT and liver were collected.Results. After four weeks of MHS, the indexed heart weight was significantly increased in all groups, but to a lesser extent in mice that received Mira. The expected left atrial enlargement following the HFpEF-inducing stress, MHS, was present in all groups, but was less in Mira male mice. Body growth was reduced in males receiving Mira. Echocardiography showed that males receiving Mira had smaller left ventricles (LV) and higher ejection fraction. Following the MHS, an expected increase in the expression of several marker genes associated with cardiac hypertrophy or fibrosis was observed in males, but not in females. Mirabegron treatment increased BAT volume in males but had a lesser effect in females. Uncoupled protein 1 (Ucp1) gene expression in the BAT was also in males but not in females. MHS alone also increased Ucp1 and β3-AR mRNA levels in BAT only in males.Conclusion. Male mouse hearts are more responsive to β3-AR activation by mirabegron, a specific agonist, than female hearts. This translates to a blunted hypertrophic response to the MHS and reduced LV expression of genes commonly increased in pathological cardiac conditions.