Sustaining Circulating Regulatory T Cell Subset Contributes to the Therapeutic Effect of Paroxetine on Mice With Diabetic Cardiomyopathy

Yongsheng Han; Jiacheng Lai; Juan Tao; Yu Tai; Weijie Zhou; Paipai Guo; Zhen Wang; Manman Wang; Qingtong Wang

doi:10.1253/circj.CJ-19-1182

Myocardial Disease

Sustaining Circulating Regulatory T Cell Subset Contributes to the Therapeutic Effect of Paroxetine on Mice With Diabetic Cardiomyopathy

Yongsheng Han, Jiacheng Lai, Juan Tao, Yu Tai, Weijie Zhou, Paipai Guo, Zhen Wang, Manman Wang, Qingtong Wang

Author information

Yongsheng Han
Department of Emergency Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China [China]
Department of Emergency Medicine, Anhui Provincial Hospital Affiliated to Anhui Medical University [China]
Jiacheng Lai
Department of Emergency Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China [China]
Department of Emergency Medicine, Anhui Provincial Hospital Affiliated to Anhui Medical University [China]
Juan Tao
Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University [China]
Yu Tai
Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University [China]
Weijie Zhou
Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University [China]
Paipai Guo
Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University [China]
Zhen Wang
Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University [China]
Manman Wang
Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University [China]
Qingtong Wang
Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University [China]

Keywords: Diabetic cardiomyopathy, G protein coupled receptor kinase 2, Heart function, Regulatory T cell, Th17

JOURNAL OPEN ACCESS FULL-TEXT HTML

2020 Volume 84 Issue 9 Pages 1587-1598

DOI https://doi.org/10.1253/circj.CJ-19-1182

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Abstract

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.

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