Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland.
Circulation. 2012 Dec 18;126(25):2962-75. doi: 10.1161/CIRCULATIONAHA.112.093906. Epub 2012 Nov 7.
MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34(+) 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 angiogenesis, in angiogenic EOCs and circulating CD34(+) cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity.
Angiogenic EOCs and CD34(+) cells were isolated from patients with CHF caused by ischemic cardiomyopathy (n=45) and healthy subjects (n=35). 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(+) 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.
The present study reveals a loss of angiomiR-126 and -130a in angiogenic EOCs and circulating CD34(+) 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.
MicroRNAs 是血管生成过程的关键调节因子。给予血管生成早期外胚层细胞 (EOCs) 或 CD34(+) 细胞已被建议改善缺血性损伤后的心脏功能，特别是通过促进血管新生。因此，本研究检测了参与血管生成的血管生成 miR，即 microRNAs 在血管生成 EOCs 和慢性心力衰竭 (CHF) 患者循环 CD34(+) 细胞中的表达调节及其对心脏修复能力的作用。
从缺血性心肌病引起的 CHF 患者 (n=45) 和健康受试者 (n=35) 中分离出血管生成 EOCs 和 CD34(+) 细胞。在流式细胞术分析中，血管生成 EOCs 主要是髓样细胞，并且对替代性激活的 M2 巨噬细胞标志物呈阳性。在心肌梗死的裸鼠体内进行心脏新生血管形成和功能修复能力的检测。来自健康受试者的血管生成 EOCs 的心脏移植显著增加了新生血管形成并改善了心脏功能，而来自 CHF 患者的血管生成 EOCs 的心脏移植则没有观察到这种效果。对血管生成 EOCs 中表达的 14 种候选血管生成 miR 的实时聚合酶链反应分析显示，CHF 患者的血管生成 EOCs 中明显丢失了血管生成 miR-126 和 -130a，这在循环 CD34(+) 细胞中也观察到。抗 miR-126 转染显著损害了健康受试者来源的血管生成 EOCs 改善心脏功能的能力。miR-126 模拟转染增加了 CHF 患者来源的血管生成 EOCs 改善心脏新生血管形成和功能的能力。
本研究揭示了 CHF 患者的血管生成 EOCs 和循环 CD34(+) 细胞中血管生成 miR-126 和 -130a 的缺失。降低的 miR-126 表达被确定为限制其改善心脏新生血管形成和功能能力的新机制，可以通过 miR-126 模拟转染靶向。
