Circulating myocardial microRNAs from infarcted hearts are carried in exosomes and mobilise bone marrow progenitor cells

Abstract

Myocardial microRNAs (myo-miRs) are released into the circulation after acute myocardial infarction (AMI). How they impact remote organs is however largely unknown. Here we show that circulating myo-miRs are carried in exosomes and mediate functional crosstalk between the ischemic heart and the bone marrow (BM). In mice, we find that AMI is accompanied by an increase in circulating levels of myo-miRs, with miR-1, 208, and 499 predominantly in circulating exosomes and miR-133 in the non-exosomal component. Myo-miRs are imported selectively to peripheral organs and preferentially to the BM. Exosomes mediate the transfer of myo-miRs to BM mononuclear cells (MNCs), where myo-miRs downregulate CXCR4 expression. Injection of exosomes isolated from AMI mice into wild-type mice downregulates CXCR4 expression in BM-MNCs and increases the number of circulating progenitor cells. Thus, we propose that myo-miRs carried in circulating exosomes allow a systemic response to cardiac injury that may be leveraged for cardiac repair.

Potential roles of microRNA-1 and microRNA-133 in cardiovascular disease

“…Several studies have confirmed the potential of circulating miR-208a and miR-208b, miR-499, miR-133a and miR-1 as sensitive and specific biomarkers of cardiac injury in cardiovascular disease (Fung et al, 2019;Islas and Moreno-Cuevas, 2018;Shi and Yang, 2016). Furthermore, circulating miR-133 and miR-1 participate in the mobilization of progenitor cells and other accessory cells from bone marrow to the peripheral circulation, which is the key procedure in the recovery of cardiac function after cardiac ischemic injury (Cheng et al, 2019).…”

“…Exosome-miRNAs are selectively and preferentially transferred to bone marrow monocytes where they (miR-1a, not miR-133a, miR-499 or miR-208, directly target the 3' UTR of CXC chemokine receptor 4 (CXCR4)) inhibit the expression of CXCR4 and mediate progenitor cell mobilization. Mobilizing progenitor cells and other accessory cells in bone marrow to peripheral circulation is a key procedure in the recovery of cardiac function after cardiac ischemic injury (Cheng et al, 2019).…”

“…Among the four miRNAs upregulated after myocardial infarction, miR133a has the strongest inhibitory effect on the expression of CXCR4, and the concentration of miR133a is the highest in circulation. Although miR133a is only partially carried by exosome, it may have more powerful functions (Cheng et al, 2019). Phosphoprotein 1 secreted by fibroblasts can protect miRNA from degradation in vitro, but it remains to be confirmed whether phosphoprotein 1 plays a role in transporting miRNAs in vivo (Arroyo et al, 2011).…”

Exosomes as a Source of Cancer Biomarkers: Advances in Electrochemical Biosensing of Exosomes

“…Exosomes secreted by stem cells act as inhibitors of tumour angiogenesis and modulators of a tumour secretome and growth . Circulating myocardial microRNAs carried by exosomes are responsible for the cross‐talk between ischemic heart and bone marrow and thereby make possible the systemic response to cardiac injury required for cardiac repair and circulating microRNAs were involved in signalling causing pre‐term birth in mice . Since exosomes can carry cargo across the blood‐brain barrier and they lack an immune response, they play an important role in the development and progression of neurodegenerative and mental diseases, as well as in neurophysiological processes .…”

Emerging Challenges of Radiation-Associated Cardiovascular Dysfunction (RACVD) in Modern Radiation Oncology: Clinical Practice, Bench Investigation, and Multidisciplinary Care

“…In the literature, many clinical studies assessed circulating miRNA levels in peripheral blood for diagnosing, predicting, and monitoring human diseases (158)(159)(160)(161)(162)(163), including cardiac and vascular disease (CVD) (164)(165)(166)(167)(168)(169). For example, the combination of miR-34a-5p and fibrinogen levels have been reported as a useful tool in differentiating pre-thrombotic status in patients with stable coronary artery disease (165).…”