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

Background: Dilated 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 results: EVs 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. Conclusions: EVs 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. [ABSTRACT FROM AUTHOR]