Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, China.
Immun Inflamm Dis. 2024 Nov;12(11):e70073. doi: 10.1002/iid3.70073.
Viral myocarditis (VMC) plays a significant role in heart failure, and there is currently a shortage of available targeted treatments. Macrophage phenotype and function are closely associated with the beta-2 adrenergic receptor (β2-AR).
This research employed a BALB/c mouse model of VMC generated using Coxsackievirus B3 (CVB3), and the β2-AR agonist formoterol was administered as treatment. A bioinformatic analysis was conducted to identify the β2-AR in CCR2MHCII monocyte-derived macrophages (MoMFs). Echocardiography and histopathological assessments were utilized to evaluate cardiac function and inflammation. The enzymatic activity of glutaminase (GLS) was quantified. Flow cytometry was employed to characterize the phenotype and function of the macrophages.
Our study revealed that formoterol treatment effectively mitigated cardiac inflammation and fibrosis, improved cardiac function, and prolonged survival compared to the VMC group. Formoterol reduced the infiltration of CCR2MHCII MoMFs in the heart, inhibited M1 phenotypic expression and activity, and reduced the percentage of Ly6C monocytes in circulation. Additionally, formoterol stimulated M2 phenotypic expression and activity and increased the percentage of Ly6C monocytes in circulation. Additionally, the combination of NICB3344, a C-C motif chemokine receptor 2 inhibitor, with formoterol did not exhibit synergistic effects on reducing cardiac pathological scores or enhancing cardiac function. In vitro studies involving the use of lipopolysaccharide (LPS)-induced bone marrow-derived macrophages, revealed the ability of formoterol to suppress the M1 phenotype and functions induced by LPS while promoting the M2 phenotype and functions. Nevertheless, the observed effects were negated by the introduction of the GLS inhibitor BPTES.
Formoterol potentially serves as a significant metabolic regulator in the differentiation process of cardiac MoMFs, influencing this process by controlling GLS activity. Targeting β2-AR exhibits potential as an effective approach for managing VMC. It is essential to acknowledge that these findings were derived under specific experimental conditions, with the current conclusions predominantly based on animal models. Future research is necessary to further investigate the feasibility of formoterol in clinical practice.
病毒性心肌炎（VMC）在心力衰竭中起着重要作用，目前可用的靶向治疗方法短缺。巨噬细胞表型和功能与β2 肾上腺素能受体（β2-AR）密切相关。
本研究采用柯萨奇病毒 B3（CVB3）建立 BALB/c 小鼠 VMC 模型，并给予β2-AR 激动剂福莫特罗进行治疗。通过生物信息学分析鉴定 CCR2MHCII 单核细胞衍生巨噬细胞（MoMFs）中的β2-AR。采用超声心动图和组织病理学评估评估心脏功能和炎症。定量测定谷氨酰胺酶（GLS）的酶活性。采用流式细胞术对巨噬细胞的表型和功能进行特征分析。
与 VMC 组相比，福莫特罗治疗可有效减轻心脏炎症和纤维化，改善心脏功能，延长存活时间。福莫特罗减少了心脏中 CCR2MHCII MoMF 的浸润，抑制了 M1 表型表达和活性，减少了循环中 Ly6C 单核细胞的百分比。此外，福莫特罗刺激 M2 表型表达和活性，增加了循环中 Ly6C 单核细胞的百分比。此外，CC motif 趋化因子受体 2 抑制剂 NICB3344 与福莫特罗联合使用并未显示出在降低心脏病理评分或增强心脏功能方面的协同作用。使用脂多糖（LPS）诱导的骨髓来源巨噬细胞进行的体外研究表明，福莫特罗能够抑制 LPS 诱导的 M1 表型和功能，同时促进 M2 表型和功能。然而，引入 GLS 抑制剂 BPTES 则否定了这些观察结果。
福莫特罗可能是心脏 MoMF 分化过程中的重要代谢调节剂，通过控制 GLS 活性影响这一过程。靶向β2-AR 作为治疗 VMC 的有效方法具有潜力。需要注意的是，这些发现是在特定的实验条件下得出的，目前的结论主要基于动物模型。未来的研究有必要进一步研究福莫特罗在临床实践中的可行性。
