Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury: Role of Human CD34⁺ Cells Deficient in MicroRNA-377

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• 作者：Darukeshwara Joladarashi ; PhD^&lowast ; ; Venkata Naga Srikanth Garikipati ; PhD^&dagger ; ; Rajarajan A. Thandavarayan ; PhD^&lowast ; ; Suresh K. Verma ; PhD^&dagger ; ; Alexander R. Mackie ; PhD^&Dagger ; ; Mohsin Khan ; PhD^&dagger ; ; Anna M. Gumpert ; PhD^&dagger ; ; Arvind Bhimaraj ; MD^§ ; ; Keith A. Youker ; PhD^§ ; ; Cesar Uribe ; MD^§ ; ; Sahana Suresh Babu ; PhD^&lowast ; ; Prince Jeyabal ; PhD^&lowast ; ; Raj Kishore ; PhD^&dagger ; ; Prasanna Krishnamurthy ; PhD^&lowast ; ; ^‖ ; ^{pkrishnamurthy@houstonmethodist.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：endothelial progenitor cells ; heart failure ; neovascularization
• 刊名：Journal of the American College of Cardiology
• 出版年：2015
• 出版时间：17-24 November 2015
• 年：2015
• 卷：66
• 期：20
• 页码：2214-2226
• 全文大小：3925 K

文摘

MicroRNA (miR) dysregulation in the myocardium has been implicated in cardiac remodeling after injury or stress.

Objectives

The aim of this study was to explore the role of miR in human CD34⁺ cell (hCD34⁺) dysfunction in vivo after transplantation into the myocardium under ischemia-reperfusion (I-R) conditions.

Methods

In response to inflammatory stimuli, the miR array profile of endothelial progenitor cells was analyzed using a polymerase chain reaction–based miR microarray. miR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF). We investigated the effect of miR-377 inhibition on an hCD34⁺ cell angiogenic proteome profile in vitro and on cardiac repair and function after I-R injury in immunodeficient mice.

Results

The miR array data from endothelial progenitor cells in response to inflammatory stimuli indicated changes in numerous miR, with a robust decrease in the levels of miR-377. Human cardiac biopsies from patients with HF showed significant increases in miR-377 expression compared with nonfailing control hearts. The proteome profile of hCD34⁺ cells transfected with miR-377 mimics showed significant decrease in the levels of proangiogenic proteins versus nonspecific control–transfected cells. We also validated that serine/threonine kinase 35 is a target of miR-377 using a dual luciferase reporter assay. In a mouse model of myocardial I-R, intramyocardial transplantation of miR-377 silenced hCD34⁺ cells in immunodeficient mice, promoting neovascularization (at 28 days, post–I-R) and lower interstitial fibrosis, leading to improved left ventricular function.

Conclusions

These findings indicate that HF increased miR-377 expression in the myocardium, which is detrimental to stem cell function, and transplantation of miR-377 knockdown hCD34⁺ cells into ischemic myocardium promoted their angiogenic ability, attenuating left ventricular remodeling and cardiac fibrosis.