Heart Failure Loss of AngiomiR-126 and 130a in Angiogenic Early Outgrowth Cells From Patients With Chronic Heart Failure Role for Impaired In Vivo Neovascularization and Cardiac Repair Capacity

Background—MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34 ϩ cells has been suggested to improve cardiac function after ischemic injury, in particular by promoting neovascularization. The present study therefore examines regulation of angiomiRs, microRNAs involved in angiogen-esis, in angiogenic EOCs and circulating CD34 ϩ cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity. Methods and Results—Angiogenic EOCs and CD34 ϩ cells were isolated from patients with CHF caused by ischemic cardiomyopathy (nϭ45) and healthy subjects (nϭ35). In flow cytometry analyses, angiogenic EOCs were largely myeloid and positive for alternatively activated M2 macrophage markers. In vivo cardiac neovascularization and functional repair capacity were examined after transplantation into nude mice with myocardial infarction. Cardiac transplantation of angiogenic EOCs from healthy subjects markedly increased neovascularization and improved cardiac function, whereas no such effect was observed after transplantation of angiogenic EOCs from patients with CHF. Real-time polymerase chain reaction analysis of 14 candidate angiomiRs, expressed in angiogenic EOCs, revealed a pronounced loss of angiomiR-126 and-130a in angiogenic EOCs from patients with CHF that was also observed in circulating CD34 ϩ cells. Anti–miR-126 transfection markedly impaired the capacity of angiogenic EOCs from healthy subjects to improve cardiac function. miR-126 mimic transfection increased the capacity of angiogenic EOCs from patients with CHF to improve cardiac neovascularization and function. Conclusions—The present study reveals a loss of angiomiR-126 and-130a in angiogenic EOCs and circulating CD34 ϩ cells from patients with CHF. Reduced miR-126 expression was identified as a novel mechanism limiting their capacity to improve cardiac neovascularization and function that can be targeted by miR-126 mimic transfection. M icroRNAs (miRNAs), small noncoding RNAs regulating gene expression at the posttranscriptional level, have recently been identified as key regulators of angiogenic processes. 1– 4 Endothelial silencing of Dicer, an RNase-III enzyme required for generation of mature miRNAs, revealed a critical role of miRNAs for in vitro and in vivo angiogenic processes. 5,6 Furthermore, individual miRNAs, including miR-126, miR-130a, let-7f, and the miR-17–92 cluster, have been identified as key positive or negative regulators of angiogenic processes. 5,7–13 Accumulating data suggest that bone marrow– derived mononuclear cells are important regulators of cardiac neo-vascularization. 14 –24 In particular, several studies have demonstrated that administration of angiogenic early outgrowth cells (EOCs), also known as circulating angiogenic cells, or CD34 ϩ cells stimulate myocardial neovascularization and improve cardiac function after …