Myocardial Injection of Apelin-Overexpressing Bone Marrow Cells Improves Cardiac Repair via Upregulation of Sirt3 after Myocardial Infarction
Chen J-X (2013) Myocardial Injection of Apelin-Overexpressing Bone Marrow Cells Improves Cardiac Repair via Upregulation
of Sirt3 after Myocardial Infarction. PLoS ONE 8(9): e71041. doi:10.1371/journal.pone.0071041
Myocardial Injection of Apelin-Overexpressing Bone Marrow Cells Improves Cardiac Repair via Upregulation of Sirt3 after Myocardial Infarction
Lanfang Li. 0
Heng Zeng. 0
Xuwei Hou 0
Xiaochen He 0
Jian-Xiong Chen 0
Tim Lahm, Indiana University, United States of America
0 Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi , United States of America
Our previous study shows that treatment with apelin increases bone marrow cells (BMCs) recruitment and promotes cardiac repair after myocardial infarction (MI). The objective of this study was to investigate whether overexpression of apelin in BMCs improved cell therapy and accelerated cardiac repair and functional recovery in post-MI mice. Mouse myocardial infarction was achieved by coronary artery ligation and BMCs overexpressing apelin (apelin-BMCs) or GFP (GFP-BMCs) were injected into ischemic area immediately after surgery. In vitro, exposure of cultured BMCs to apelin led to a gradual increase in SDF-1a and CXCR4 expression. Intramyocardial delivery of apelin-BMCs in post-MI mice resulted in a significant increase number of APJ+/c-kit+/Sca1+ cells in the injected area compared to GFP-BMCs treated post-MI mice. Treatment with apelinBMCs increased expression of VEGF, Ang-1 and Tie-2 in post-MI mice. Apelin-BMCs treatment also significantly increased angiogenesis and attenuated cardiac fibrosis formation in post-MI mice. Most importantly, treatment with apelin-BMCs significantly improved left ventricular (LV) systolic function in post-MI mice. Mechanistically, Apelin-BMCs treatment led to a significant increase in Sirtuin3 (Sirt3) expression and reduction of reactive oxygen species (ROS) formation. Treatment of cultured BMCs with apelin also increased Notch3 expression and Akt phosphorylation. Apelin treatment further attenuated stress-induced apoptosis whereas knockout of Sirt3 abolished anti-apoptotic effect of apelin in cultured BMCs. Moreover, knockout of Sirt3 significantly attenuated apelin-BMCs-induced VEGF expression and angiogenesis in post-MI mice. Knockout of Sirt3 further blunted apelin-BMCs-mediated improvement of cardiac repair and systolic functional recovery in post-MI mice. These data suggest that apelin improves BMCs therapy on cardiac repair and systolic function in post-MI mice. Upregulation of Sirt3 may contribute to the protective effect of apelin-BMCs therapy.
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Funding: This study was supported by grants from the National Institutes of Health, grant HL102042. The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
. These authors contributed equally to this work.
Both experimental and clinical studies show that treatment of
myocardial ischemia with bone marrow derived cells (BMCs)
reduces infarct size and improves cardiac function [1,2]. BMCs
have been identified as promising candidate for use as cell based
therapy for cardiac regeneration and repair after myocardial
infarction (MI) [3,4]. However, one of the significant problems
with BMCs therapy is cell survival. Myocardial ischemia creates a
hostile environment due to locally increased reactive oxygen
species (ROS) formation inducing cell apoptosis. Accumulative
evidence reveals that survival of the injected BMCs is very low,
especially in post-MI hearts. To circumvent this shortcoming of
cell based therapy in ischemic hearts, one of the therapeutic
approaches is overexpression of mesenchymal stem cells with
prosurvival factors. Overexpression of mesenchymal stem cells with
Akt or glycogen synthase kinase-3 (GSK-3) in ex vivo increases the
survival of mesenchymal stem cells after transplantation and
significantly improves cardiac function in post-MI mice [5,6].
These studies suggest that a combination of BMCs and gene
therapy may be attractive strategy to boost BMCs-based cell
therapies for heart failure.
Apelin is an endogenous ligand for the angiotensin-like 1
receptor (APJ) and has beneficial effects against myocardial
ischemia/reperfusion injury [710]. Transplantation of BMCs
led to a significant increase in apelin level and improvement of
cardiac function in patients with severe heart failure [11]. In
contrast, loss of apelin and APJ function impairs differentiations of
endothelial, hematopoietic and cardiac progenitor cell [12,13].
Treatment of BMCs with apelin also attenuates starvation-induced
bone marrow mesenchymal cells apoptosis via activation of PI3k/
Akt pathway [14]. Our recent study demonstrated that treatment
with apelin led to a significant increase in homing of BMC derived
vascular progenitor cells and improvement of cardiac function in
post-M (...truncated)