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.

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心肌病 (DCM)。GRK2 也参与调节 T 细胞功能；帕罗西汀对 DCM 免疫反应的潜在修饰尚不清楚。

方法和结果：DCM 小鼠由高脂肪饮食 (HFD) 喂养诱导。流式细胞术发现 DCM 小鼠的调节性 T (Treg) 细胞亚群显着减少，超声心动图评估心脏功能受损。受抑制的 Treg 分化可归因于以 GRK2-PI3K-Akt 信号依赖方式的胰岛素慢性刺激。选择性 GRK2 抑制剂帕罗西汀在体外和体内挽救了 Treg 分化。此外，与载体治疗的 DCM 小鼠相比，帕罗西汀治疗的 DCM 小鼠的心脏功能以及兴奋-收缩偶联蛋白（如磷素 (PLB) 和肌钙蛋白 I (TnI)）的激活得到有效促进。阻断 FoxP3 表达足以抑制 Treg 细胞的比例，消除了帕罗西汀对 HFD 喂养小鼠心脏功能以及 PLB 和 TnI 活化的保护作用。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 小鼠受损的心脏收缩功能，部分是通过靶向 GRK2-PI3K-Akt 通路恢复循环 Treg 细胞的数量。