TY - JOUR
T1 - Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury
T2 - Role of Human CD34(+) Cells Deficient in MicroRNA-377
AU - Joladarashi, Darukeshwara
AU - Srikanth Garikipati, Venkata Naga
AU - Thandavarayan, Rajarajan A
AU - Verma, Suresh K
AU - Mackie, Alexander R
AU - Khan, Mohsin
AU - Gumpert, Anna M
AU - Bhimaraj, Arvind
AU - Youker, Keith A
AU - Uribe, Cesar
AU - Suresh Babu, Sahana
AU - Jeyabal, Prince
AU - Kishore, Raj
AU - Krishnamurthy, Prasanna
N1 - Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PY - 2015/11/17
Y1 - 2015/11/17
N2 - 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.
AB - 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.
KW - endothelial progenitor cells
KW - heart failure
KW - neovascularization
UR - http://www.scopus.com/inward/record.url?scp=84946782417&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84946782417&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2015.09.009
DO - 10.1016/j.jacc.2015.09.009
M3 - Article
C2 - 26564600
SN - 0735-1097
VL - 66
SP - 2214
EP - 2226
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 20
ER -