The effects of extracellular vesicles derived from Kr\xfcppel-Like Factor 2 overexpressing endothelial cells on the regulation of cardiac inflammation in the dilated cardiomyopathy

Wenfeng Zhang,Ziwei Chen,Xuan Wei,Hongyan Zheng,Qiaoling Li,Wei Huang,Shuaihua Qiao,Biao Xu,Siyuan Chen

doi:10.1186/s12951-022-01284-1

Wenfeng Zhang, Ziwei Chen + Show 7 more

Open Access

https://doi.org/10.1186/s12951-022-01284-1

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Abstract

BackgroundDilated cardiomyopathy (DCM) is one of the common causes of heart failure. Myocardial injury triggers an inflammatory response and recruits immune cells into the heart. High expression of Krüppel-like factor 2 (KLF2) in endothelial cells (ECs) potentially exerts an anti-inflammatory effect. However, the role of extracellular vesicles (EVs) from KLF2-overexpressing ECs (KLF2-EVs) in DCM remains unclear.Methods and resultsEVs were separated from the supernatant of KLF2-overexpressing ECs by gradient centrifugation. Mice were repeatedly administered low-dose doxorubicin (DOX) and then received KLF2-EVs through an intravenous injection. Treatment with KLF2-EVs prevented doxorubicin-induced left ventricular dysfunction and reduced the recruitment of Ly6high Mo/Mø in the myocardium. We used flow cytometry to detect Ly6high monocytes in bone marrow and spleen tissues and to elucidate the mechanisms underlying this beneficial effect. KLF2-EVs increased the retention of Ly6Chigh monocytes in the bone marrow but not in the spleen tissue. KLF2-EVs also significantly downregulated C–C chemokine receptor 2 (CCR2) protein expression in cells from the bone marrow.ConclusionsEVs derived from KLF2-overexpressing ECs reduced cardiac inflammation and ameliorated left ventricular dysfunction in DCM mice by targeting the CCR2 protein to inhibit Ly6Chigh monocyte mobilization from the bone marrow.Graphical

Highlights

Dilated cardiomyopathy (DCM) is one of the common causes of heart failure
extracellular vesicles (EVs) derived from Krüppel-like factor 2 (KLF2)-overexpressing endothelial cells (ECs) reduced cardiac inflammation and ameliorated left ventricular dysfunction in DCM mice by targeting the chemokine receptor 2 (CCR2) protein to inhibit Ly6Chigh monocyte mobilization from the bone marrow
Mice in the DCM group received an intraperitoneal injection of doxorubicin (DOX) (20 mg/kg in total) dissolved in saline, whereas mice in the control group were injected with an equal quantity of saline. 7 days after the DOX injection, mice in the DCM group were randomly divided into the DCM + KLF2-EVs group and DCM + phosphate-buffered saline (PBS) group

Summary

Introduction

Myocardial injury triggers an inflammatory response and recruits immune cells into the heart. High expression of Krüppel-like factor 2 (KLF2) in endothelial cells (ECs) potentially exerts an anti-inflammatory effect. The role of extracellular vesicles (EVs) from KLF2-overexpressing ECs (KLF2-EVs) in DCM remains unclear. Several studies have indicated that the inflammatory response and immune cells play important roles in the process of DCM [6,7,8]. KLF2 was expressed at high levels in ECs under laminar flow conditions, which showed an anti-inflammatory phenotype [11, 12]. Previous studies from our group revealed that KLF2-overexpressing ECs effectively preserve the anti-inflammatory phenotype and contribute to regulating immunity by secreting extracellular vesicles (EVs) [13]

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