Sustaining Circulating Regulatory T Cell Subset Contributes to the Therapeutic Effect of Paroxetine on Mice With Diabetic Cardiomyopathy
Sustaining Circulating Regulatory T Cell Subset Contributes to the Therapeutic Effect of Paroxetine on Mice With Diabetic Cardiomyopathy
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DOI：
10.1253/circj.cj-19-1182
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发表时间：
2020-09-01
影响因子：
3.3
通讯作者：
Wang, Qingtong
中科院分区：
文献类型：
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作者：
Han, Yongsheng;Lai, Jiacheng;Wang, Qingtong
背景：G蛋白偶联受体激酶2 （GRK2）抑制剂帕罗西汀已被批准用于改善糖尿病性心肌病（DCM）。GRK2还参与调节T细胞功能；帕罗西汀对DCM免疫应答的潜在影响尚不清楚。方法与结果：采用高脂饲料（HFD）诱导DCM小鼠。流式细胞术发现DCM小鼠的调节性T （Treg）细胞亚群显著减少，超声心动图评估心功能受损。抑制Treg分化可归因于胰岛素慢性刺激以GRK2-PI3K-Akt信号依赖的方式。选择性GRK2抑制剂帕罗西汀在体外和体内都能挽救Treg的分化。此外，帕罗西汀处理的DCM小鼠的心脏功能以及兴奋-收缩偶联蛋白（如磷蛋白（PLB）和肌钙蛋白I (TnI)）的激活与药物处理的DCM小鼠相比得到了有效的促进。阻断FoxP3表达充分抑制Treg细胞的比例，消除帕罗西汀对hfd小鼠心功能的保护作用以及PLB和TnI的激活。帕罗西汀和卡维地洛均不能有效改善HFD小鼠的代谢紊乱。结论：帕罗西汀治疗可有效改善DCM小鼠收缩心功能受损，部分原因是通过靶向GRK2-PI3K-Akt通路恢复循环Treg细胞群。
Background: G protein coupled receptor kinase 2 (GRK2) inhibitor, paroxetine, has been approved to ameliorate diabetic cardiomyopathy (DCM). GRK2 is also involved in regulating T cell functions; the potential modifications of paroxetine on the immune response to DCM is unclear.Methods and Results: DCM mouse was induced by high-fat diet (HFD) feeding. A remarkable reduction in the regulatory T (Treg) cell subset in DCM mouse was found by flow cytometry, with impaired cardiac function evaluated by echocardiography. The inhibited Treg differentiation was attributable to insulin chronic stimulation in a GRK2-PI3K-Akt signaling-dependent manner. The selective GRK2 inhibitor, paroxetine, rescued Treg differentiation in vitro and in vivo. Furthermore, heart function, as well as the activation of excitation-contraction coupling proteins such as phospholamban (PLB) and troponin I (TnI) was effectively promoted in paroxetine-treated DCM mice compared with vehicle-treated DCM mice. Blockade of FoxP3 expression sufficiently inhibited the proportion of Treg cells, abolished the protective effect of paroxetine on heart function as well as PLB and TnI activation in HFD-fed mice. Neither paroxetine nor carvedilol could effectively ameliorate the metabolic disorder of HFD mice.Conclusions: The impaired systolic heart function of DCM mice was effectively improved by paroxetine therapy, partially through restoring the population of circulating Treg cells by targeting the GRK2-PI3K-Akt pathway.