The GABAA Receptor Influences Pressure Overload-Induced Heart Failure by Modulating Macrophages in Mice

Jin Bu; Shiyuan Huang; Jue Wang; Tong Xia; Hui Liu; Ya You; Zhaohui Wang; Kun Liu

doi:10.3389/fimmu.2021.670153

The GABA_A Receptor Influences Pressure Overload-Induced Heart Failure by Modulating Macrophages in Mice

Front Immunol. 2021 May 31:12:670153. doi: 10.3389/fimmu.2021.670153. eCollection 2021.

Authors

Jin Bu¹, Shiyuan Huang², Jue Wang³, Tong Xia², Hui Liu², Ya You², Zhaohui Wang², Kun Liu⁴

Affiliations

¹ Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Institution of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

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^lowMHCII^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.

Keywords: GABAA receptor; amphiregulin; macrophage; monocyte; pressure-overload hypertrophy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta / physiopathology
Aorta / surgery
Arterial Pressure
Disease Models, Animal
Fibrosis
GABA-A Receptor Antagonists / pharmacology*
Heart Failure / drug therapy*
Heart Failure / etiology
Heart Failure / metabolism
Heart Failure / physiopathology
Hypertrophy, Left Ventricular / drug therapy*
Hypertrophy, Left Ventricular / etiology
Hypertrophy, Left Ventricular / metabolism
Hypertrophy, Left Ventricular / physiopathology
Ligation
Macrophages / drug effects*
Macrophages / metabolism
Male
Mice
Mice, Inbred C57BL
Myocardium / metabolism
Myocardium / pathology
Receptors, GABA-A / drug effects*
Receptors, GABA-A / metabolism
Signal Transduction
Ventricular Function, Left / drug effects
Ventricular Remodeling / drug effects

Substances

GABA-A Receptor Antagonists
Receptors, GABA-A