Dendritic cell‑derived exosomal miR‑494‑3p promotes angiogenesis following myocardial infarction

Abstract

Infiltration by dendritic cells (dcs) is markedly increased in the infarcted area following myocardial infarction (MI), and dc ablation has been shown to impair angiogenesis in mice post-MI. Exosomes (EXs) have long been known to act as messengers between cells; however, whether EXs derived from dcs can enhance myocardial angiogenesis post-MI remains unknown. The aim of the present study was to elucidate whether EXs derived from dcs induce myocardial angiogenesis via paracrine signaling post-MI. In vitro, suspensions of mouse bone marrow-derived dcs (BMdcs) were incubated with the supernatant of necrotic or normal cultured HL-1 myocardial cells (as the MI or control group, respectively) for 24 h. EXs isolated from the supernatant of BMdcs were termed dEXs, which were added to primary cultures of rat cardiac microvascular endothelial cells (cMEcs), and angiogenesis was evaluated by measuring tube formation and vascular endothelial growth factor (VEGF) expression. In vivo, different groups of dEXs were injected into the infarcted myocardium of MI model mice. Then, angiogenesis was evaluated by measuring the number of vessels and the expression of VEGF and cd31 in the infarcted myocardium using immunohistochemistry. Moreover, the expression profile of microRNAs (miRNAs or miRs) in splenic dcs of MI model mice was analyzed by Affymetrix miRNA 4.0 chip assays, then certified in DEXs by reverse transcription-quantitative PcR analysis. Finally, miRNA-loaded dEXs were used to induce tube formation by cMEcs and angiogenesis in MI model mice. It was observed that, compared with the control group, DEXs from the MI group significantly upregulated the expression of VEGF in cMEcs, enhanced tube formation by cMEcs, and upregulated the expression of VEGF and cd31 in the infarcted myocardium of MI model mice. miR-494-3p and miR-16a-5p, which are associated with angiogenesis, were significantly upregulated in splenic DCs of MI model mice by Affymetrix miRNA 4.0 chip assays, miR-494-3p was significantly upregulated and highly enriched in dEXs from the MI group compared with the control, and dEX-miR-494-3p enhanced tube formation by cMEcs and angiogenesis in mice post-MI. These results suggest that miR-494-3p may be secreted from dcs via EXs and promotes angiogenesis post-MI. These findings indicate a novel DEX-based approach to the treatment of MI.

The effect of immune cell‐derived exosomes in the cardiac tissue repair after myocardial infarction: Molecular mechanisms and pre‐clinical evidence

“…Recently, it has been shown that the DCs infiltrating the infarcted myocardium following MI could induce angiogenesis by secreting the EXs containing highly expressed angiogenic miRs, particularly miR-494-3p. 52 It was found that miR-494-3-enriched MI-DC-EXs could be directly taken up by the cardiac microvascular endothelial cells (CMECs), significantly up-regulate the expression of the VEGF in CMECs, and thereby enhance angiogenesis in the infarcted myocardium after experimental MI. 52 In conclusion, MI-DC-EXs can promote recovery of the injured myocardium and improve cardiac function after MI through activating CD4 + Foxp3 + Tregs cells and inducing angiogenesis, providing a potent strategy for the treatment of MI.…”

“…Besides, there is evidence showing the key role of DC‐EXs in angiogenesis following MI. 52 During the early phase after MI, angiogenesis plays an important role in the recovery of the injured myocardium and myocardial remodelling as well as maintenance of cardiac function 53 , 54 through healing the microvascular bed and preventing further necrosis and apoptosis of ischaemic myocardial tissue, which may be damaged, hibernating or stunned following MI. 53 Notably, DC ablation has been found to deteriorate angiogenesis and cardiac function in mice post‑MI, 12 supporting the determinant role of DCs in angiogenesis and cardiac healing after MI.…”

“… 52 It was found that miR‑494‑3‐enriched MI‐DC‐EXs could be directly taken up by the cardiac microvascular endothelial cells (CMECs), significantly up‐regulate the expression of the VEGF in CMECs, and thereby enhance angiogenesis in the infarcted myocardium after experimental MI. 52 …”

“…Of note, DC‐EXs are one of the critical factors that mediate such an effect. Recently, it has been shown that the DCs infiltrating the infarcted myocardium following MI could induce angiogenesis by secreting the EXs containing highly expressed angiogenic miRs, particularly miR‑494‑3p 52 . It was found that miR‑494‑3‐enriched MI‐DC‐EXs could be directly taken up by the cardiac microvascular endothelial cells (CMECs), significantly up‐regulate the expression of the VEGF in CMECs, and thereby enhance angiogenesis in the infarcted myocardium after experimental MI 52 …”

Exosomes and Micro-RNAs in Aging Process

“…Recently, they were suggested as biomarkers for several diseases to set up diagnosis and disease progression. Their characteristics hold a great interest in designing therapeutic purposes in metabolic and genetic disorders, neurodegenerative and cardiovascular diseases, and cancer [12][13][14][15]. Nevertheless, different characterizations and validation methods have been developed whereby exosome purification and drug delivery are improved [1,[15][16][17].…”