Department of Cardiology, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Shandong, China; Department of Cardiology, Zibo Central Hospital, Zibo City, Shandong Province, China.
Department of Cardiology, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Shandong, China; Translational Medical Research Center, the First Hospital Affiliated to Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, China.
Rev Port Cardiol. 2023 Feb;42(2):125-135. doi: 10.1016/j.repc.2021.10.011. Epub 2022 Aug 10.
INTRODUCTION & OBJECTIVES: Acute myocardial infarction (AMI) in coronary heart disease is a leading cause of sudden death primarily due to malignant ventricular arrhythmias (VAs). Inflammatory cell infiltration and inflammation-induced overactivation of sympathetic nerves are the major cause of VAs in AMI pathophysiological processes. Type 2 macrophages play an anti-inflammatory role in AMI. Targeting macrophages may be a therapeutic strategy to prevent VAs post AMI. We found that gamma aminobutyric acid (GABA) promotes macrophages polarized to M2 and hypothesized that GABA might exert anti-inflammatory effects by promoting type 2 macrophage polarization in AMI. We aim to characterized GABA receptor distribution, function, and mechanisms in M2 macrophage polarization and explored the functional aspect of GABA receptor activation in sympathetic remodeling.
Gamma aminobutyric acid B receptors were expressed on macrophage surface both in vitro and in vivo. GABA receptor agonist baclofen, GABA promoted macrophage switch to M2. While GABA receptor antagonist CGP52432 blocked a baclofen induced switch to M2 polarization. GABA and baclofen increased M2 macrophage percentage and CGP52432 blocked this process in vivo. Also, IL-10 and TGF-β1 released by M2 were increased in both AMI and baclofen/AMI group; Serum NE levels were decreased by baclofen. All the above effects were reversed by CGP52432 treatment. Baclofen decreased TH and GAP-43 staining while CGP52432 enhanced their expression post AMI indicating GABA receptor activation inhibited sympathetic nerve sprouting and activity by reducing NE release.
Gamma aminobutyric acid B receptor activation promoted M2 polarization and protested AMI heart by regulating sympathetic nerve remodeling.
冠心病中的急性心肌梗死（AMI）主要是由于恶性室性心律失常（VA）导致的猝死的主要原因。炎症细胞浸润和炎症引起的交感神经过度激活是 AMI 病理生理过程中 VA 的主要原因。2 型巨噬细胞在 AMI 中发挥抗炎作用。针对巨噬细胞可能是预防 AMI 后 VA 的治疗策略。我们发现γ-氨基丁酸（GABA）促进巨噬细胞极化到 M2 型，并假设 GABA 通过促进 AMI 中 2 型巨噬细胞极化来发挥抗炎作用。我们旨在描述 GABA 受体在 M2 巨噬细胞极化中的分布、功能和机制，并探讨 GABA 受体激活在交感神经重塑中的功能方面。
体外和体内实验均显示 GABA B 受体在巨噬细胞表面表达。GABA 受体激动剂巴氯芬、GABA 促进巨噬细胞向 M2 型转换。而 GABA 受体拮抗剂 CGP52432 阻断了巴氯芬诱导的 M2 极化转换。GABA 和巴氯芬增加了 M2 巨噬细胞的比例，CGP52432 阻断了体内的这一过程。此外，AMI 和巴氯芬/AMI 组中 M2 释放的 IL-10 和 TGF-β1 增加；血清 NE 水平降低。CGP52432 治疗逆转了上述所有效应。巴氯芬减少了 TH 和 GAP-43 的染色，而 CGP52432 增强了 AMI 后它们的表达，表明 GABA 受体激活通过减少 NE 释放抑制了交感神经发芽和活性。
GABA B 受体激活通过调节交感神经重塑促进 M2 极化和预防 AMI 心脏。
