The GABAA Receptor Influences Pressure Overload-Induced Heart Failure by Modulating Macrophages in Mice
Authors: Kun Liu
Jue Wang
Tong Xia
Zhaohui Wang
Jin Bu
Shiyuan Huang
Hui Liu
Ya You
Journal: Frontiers in Immunology (2021)
Discipline: IMMUNOLOGY
Keywords: GABAA receptor; amphiregulin; macrophage; monocyte; pressure-overload hypertrophy.
Affiliations: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., 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 (GABAA) 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 GABAA 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 GABAA 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 GABAA 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 Ly6Clow macrophages in the heart during POH and circulating Ly6Chigh classic monocyte infiltration in late-phase POH. Further, topiramate drove Ly6Clow macrophages toward MHCIIhigh macrophage polarization. As a result, Ly6Clow macrophages activated the amphiregulin-induced AKT/mTOR signaling pathway, and Ly6ClowMHCIIhigh macrophage polarization increased expression levels of osteopontin and TGF-β, which led to myocardial hypertrophy and fibrosis. Conversely, GABAA receptor blockage with bicuculline reversed these effects. Conclusions: Control of the GABAA receptor activity in monocytes/macrophages plays an important role in myocardial hypertrophy and fibrosis after POH. Blockade of the GABAA receptor has the potential to improve pressure overload-induced heart failure. 

Retracted: No

PubPeer comments:
 Dear authors, could you please check the FACS plots in Fig.3A. 28 days Post -TAC Sham and Bicuculline show striking identical areas (red circles) whereas other areas lack similarity (orange circles). It would be great if you could provide the original FACS files for review. ![file] , 
 #1 Here are the two panels in question, with Bicuculline color-reversed and superimposed on 28 days Post -TAC Sham so that coinciding points cancel out. ![file] A similar relationship exists between 14-days Sham and 28-days Sham - here, again, is the 14-days panel color-reversed and superimposed on the 28-days version. ![file] , 
 **CORRECTION** Keywords: GABAA receptor, amphiregulin, macrophage, monocyte, pressure-overload hypertrophy In the original article, there was a mistake in Figure 3A and supplement 3 as published. In the Figure 3A, the representative images of Sham group at days 14 and 28 post-TAC were saved in the improper folders during editing the images and mistakenly duplicated . In the supplement 3, the representative image of Sham group at day 21 post-TAC was chosen by mistake. The corrected Figure 3A and supplement 3 appears below. Supplement 3: Living cells (upper panel) were gated to determine the presence of CD45 + Ly6G -CD11b + Ly6C high and CD45 + Ly6G -CD11b + Ly6C low monocytes at day 21 post-TAC in the peripheral blood ---- According to the correction note, the authors did not address the problems with Fig.3A 28days SHAM vs 28days Bicuculline? ,