The GABA A Receptor Influences Pressure Overload-Induced Heart Failure by Modulating Macrophages in Mice.

Background: Myocardial macrophages have key roles in cardiac remodeling and dysfunction. The gamma-aminobutyric acid subtype A (GABA _A ) receptor was recently found to be distributed in macrophages, allowing regulation of inflammatory responses to various diseases. This study aimed to clarify the role of GABA _A receptor-mediated macrophage responses in pressure overload-induced heart failure.
Methods and Results: C57BL/6J mice underwent transverse aortic constriction for pressure-overload hypertrophy (POH) and were intraperitoneally treated with a specific GABA _A receptor agonist (topiramate) or antagonist (bicuculline). Echocardiography, histology, and flow cytometry were performed to evaluate the causes and effects of myocardial hypertrophy and fibrosis. Activation of the GABA _A receptor by topiramate reduced ejection fraction and fractional shortening, enlarged the end-diastolic and end-systolic left ventricular internal diameter, aggravated myocardial hypertrophy and fibrosis, and accelerated heart failure in response to pressure overload. Mechanistically, topiramate increased the number of Ly6C ^low macrophages in the heart during POH and circulating Ly6C ^high classic monocyte infiltration in late-phase POH. Further, topiramate drove Ly6C ^low macrophages toward MHCII ^high macrophage polarization. As a result, Ly6C ^low macrophages activated the amphiregulin-induced AKT/mTOR signaling pathway, and Ly6C ^low MHCII ^high macrophage polarization increased expression levels of osteopontin and TGF-β, which led to myocardial hypertrophy and fibrosis. Conversely, GABA _A receptor blockage with bicuculline reversed these effects.
Conclusions: Control of the GABA _A receptor activity in monocytes/macrophages plays an important role in myocardial hypertrophy and fibrosis after POH. Blockade of the GABA _A receptor has the potential to improve pressure overload-induced heart failure.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Bu, Huang, Wang, Xia, Liu, You, Wang and Liu.)