Enhanced cardiac regenerative ability of stem cells after ischemia-reperfusion injury: Role of human CD34+ cells deficient in microRNA-377

Darukeshwara Joladarashi, Venkata Naga Srikanth Garikipati, Rajarajan A. Thandavarayan, Suresh K. Verma, Alexander R. Mackie, Mohsin Khan, Anna M. Gumpert, Arvind Bhimaraj, Keith A. Youker, Cesar Uribe, Sahana Suresh Babu, Prince Jeyabal, Raj Kishore, Prasanna Krishnamurthy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Background 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.

Original languageEnglish (US)
Pages (from-to)2214-2226
Number of pages13
JournalJournal of the American College of Cardiology
Volume66
Issue number20
DOIs
StatePublished - Nov 17 2015

Keywords

  • endothelial progenitor cells
  • heart failure
  • neovascularization

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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