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

Research output: Contribution to journalArticlepeer-review

39 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

Fingerprint Dive into the research topics of 'Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury: Role of Human CD34(+) Cells Deficient in MicroRNA-377'. Together they form a unique fingerprint.

Cite this