Intracardiac injection of erythropoietin induces stem cell recruitment and improves cardiac functions in a rat myocardial infarction model

Abstract

Erythropoietin (EPO) protects the myocardium from ischaemic injury and promotes beneficial remodelling. We assessed the therapeutic efficacy of intracardiac EPO injection and EPO-mediated stem cell homing in a rat myocardial infarction (MI) model. Following MI, EPO (3000 U/kg) or saline was delivered by intracardiac injection. Compared to myocardial infarction control group (MIC), EPO significantly improved left ventricular function (n= 11–14, P< 0.05) and decreased right ventricular wall stress (n= 8, P< 0.05) assessed by pressure-volume loops after 6 weeks. MI-EPO hearts exhibited smaller infarction size (20.1 ± 1.1%versus 27.8 ± 1.2%; n= 6–8, P< 0.001) and greater capillary density (338.5 ± 14.7 versus 259.8 ± 9.2 vessels per mm; n= 6–8, P< 0.001) than MIC hearts. Direct EPO injection reduced post-MI myocardial apoptosis by approximately 41% (0.27 ± 0.03%versus 0.42 ± 0.03%; n= 6, P= 0.005). The chemoattractant SDF-1 was up-regulated significantly assessed by quantitative realtime PCR and immunohistology. c-Kit+ and CD34+ stem cells were significantly more numerous in MI-EPO than in MIC at 24 hrs in peripheral blood (n= 7, P< 0.05) and 48 hrs in the infarcted hearts (n= 6, P< 0.001). Further, the mRNAs of Akt, eNOS and EPO receptor were significantly enhanced in MI-EPO hearts (n= 7, P< 0.05). Intracardiac EPO injection restores myocardial functions following MI, which may attribute to the improved early recruitment of c-Kit+ and CD34+ stem cells via the enhanced expression of chemoattractant SDF-1.

Migration of Resident Cardiac Stem Cells in Myocardial Infarction

“…Administering EPO to rats immediately after coronary occlusion (5000 IU/kg/day for 7 days) reduced cardiomyocyte loss by 50% (Calvillo et al, 2003). Recently, Klopsch et al (2009) have demonstrated that intracardiac injection of erythropoietin recruited stem cells, and improved cardiac output and ejection fraction in a rat MI model. Studies in mice by Brunner et al (2009) showed that EPO enhanced migration of stem cells to the ischemic myocardium and that this was mediated through upregulation of SDF-1 expression and the SDF-1/CXCR-4 pathway.…”

Epo and Non-hematopoietic Cells: What Do We Know?

“…Epo promotes proliferation (40,196), inhibits apoptosis (199), and facilitates differentiation of EPCs (200)(201)(202)(203). Furthermore, Epo induces mobilization of EPCs into the circulation (204,205), and their homing (155,206,207). Increased eNOS expression and BH4 biosynthesis has been shown in Epo-treated EPCs and vascular cells ( Fig.…”

Functionalized Nanomaterials

“…SDF-1a is one of the pivotal signals which can guide mature and immature stem/progenitor directional migration towards the high SDF-1a gradient and protects the stem cell from apoptosis (Jaleel et al 2004). The transient upregulation of SDF-1a level in damaged organ after injury were identified and it could stimulate stem cell mobilization from bone marrow to the injured area (Klopsch et al 2009;Ma et al 2005a). However, SDF-1a could be inactivated and cleaved in a very short half-life (<15 min) by both matrix metalloproteinase-2 (MMP-2) and CD26/dipeptidyl peptidase IV, which are two abundant proteases under inflammatory conditions (De La Luz Sierra et al 2004;McQuibban et al 2001;Peterson et al 2000).…”