Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases and Shanghai Key Laboratory of Stomatology, Shanghai, China.
National Center for Stomatology, National Clinical Research Center for Oral Diseases and Shanghai Key Laboratory of Stomatology, Shanghai, China; Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Can J Cardiol. 2023 May;39(5):593-604. doi: 10.1016/j.cjca.2023.01.013. Epub 2023 Jan 18.
Mineralocorticoid receptor (MR) antagonists have been widely used to treat heart failure (HF). Studies have shown that MR in T cells plays important roles in hypertension and myocardial hypertrophy. However, the function of T-cell MR in myocardial infarction (MI) has not been elucidated.
In this study, we used T-cell MR knockout (TMRKO) mouse to investigate the effects of T-cell MR deficiency on MI and to explore the underlying mechanisms. Echocardiography and tissue staining were used to assess cardiac function, fibrosis, and myocardial apoptosis after MI. Flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect immune cell infiltration and inflammation.
T-cell MR deficiency significantly improved cardiac function, promoted myocardial repair, and inhibited myocardial apoptosis, fibrosis, and inflammation after MI. Luminex assays revealed that TMRKO mice had significantly lower levels of interferon-gamma (IFN-γ) and interleukin-6 (IL-6) in serum and infarcted myocardium than littermate control mice. In cultured splenic T cells, MR deficiency suppressed IL-6 expression, whereas MR overexpression enhanced IL-6 expression. Chromatin immunoprecipitation (ChIP) assay demonstrated that MR bound to the MR response element on the promoter of IL-6 gene. Finally, T-cell MR deficiency significantly suppressed accumulation of macrophages in infarcted myocardium and differentiation of proinflammatory macrophages, thereby alleviating the consequences of MI.
T-cell MR deficiency improved pathologic ventricular remodelling after MI, likely through inhibition of accumulation and differentiation of proinflammatory macrophages. At the molecular level, MR may work through IFN-γ and IL-6 in T cells to exert functions in MI.
盐皮质激素受体（MR）拮抗剂已广泛用于治疗心力衰竭（HF）。研究表明，T 细胞中的 MR 在高血压和心肌肥厚中发挥重要作用。然而，T 细胞 MR 在心肌梗死（MI）中的功能尚未阐明。
在这项研究中，我们使用 T 细胞 MR 敲除（TMRKO）小鼠来研究 T 细胞 MR 缺乏对 MI 的影响，并探讨潜在机制。使用超声心动图和组织染色评估 MI 后心脏功能、纤维化和心肌细胞凋亡情况。使用流式细胞术和实时定量聚合酶链反应（qRT-PCR）检测免疫细胞浸润和炎症。
T 细胞 MR 缺乏显著改善 MI 后心脏功能，促进心肌修复，抑制心肌细胞凋亡、纤维化和炎症。Luminex 检测发现，TMRKO 小鼠血清和梗死心肌中干扰素-γ（IFN-γ）和白细胞介素-6（IL-6）水平明显低于同窝对照小鼠。在培养的脾 T 细胞中，MR 缺乏抑制 IL-6 表达，而 MR 过表达增强 IL-6 表达。染色质免疫沉淀（ChIP）检测表明，MR 结合到 IL-6 基因启动子上的 MR 反应元件。最后，T 细胞 MR 缺乏显著抑制梗死心肌中巨噬细胞的积累和促炎巨噬细胞的分化，从而减轻 MI 的后果。
T 细胞 MR 缺乏可改善 MI 后的病理性心室重构，可能通过抑制促炎巨噬细胞的积累和分化。在分子水平上，MR 可能通过 T 细胞中的 IFN-γ和 IL-6 发挥作用，从而在 MI 中发挥作用。
