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

Klopsch C, Furlani D, Gäbel R, Li W, Pittermann E, Ugurlucan M, Kundt G, Zingler C, Titze U, Wang W, Ong LL, Wagner K, Li RK, Ma N, Steinhoff G - J. Cell. Mol. Med. (2009)

Bottom Line: 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 mm2; n = 6-8, P < 0.001) than MIC hearts.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiac Surgery, University of Rostock, Germany.

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 mm2; 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.

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Direct EPO injection restored cardiac functions 6 weeks after MI assessed by catheterization. (A) Left ventricular function (Sham n= 11, MIC n= 14, MI-EPO n= 11) at both baseline and stress conditions (left panel) as well as right ventricular function (Sham n= 5, MIC n= 8, MI-EPO n= 8) at baseline condition (right panel). (B) Representative single heart beat obtained from Sham (solid loops), MIC (dashed loops) and MI-EPO (dotted loops) hearts revealed the increments of left ventricular stroke volume (LV-SV) in MI-EPO compared with MIC under baseline (upper panel) and dobutamine stress (middle panel) conditions. RV examinations (lower panel) displayed the reductions of right ventricular maximum pressure (RV-Pmax) and end-systolic pressure (RV-ESP) in MI-EPO compared with MIC under baseline conditions. *P< 0.05 MIC versus MI-EPO, **P< 0.01 MIC versus MI-EPO.
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fig01: Direct EPO injection restored cardiac functions 6 weeks after MI assessed by catheterization. (A) Left ventricular function (Sham n= 11, MIC n= 14, MI-EPO n= 11) at both baseline and stress conditions (left panel) as well as right ventricular function (Sham n= 5, MIC n= 8, MI-EPO n= 8) at baseline condition (right panel). (B) Representative single heart beat obtained from Sham (solid loops), MIC (dashed loops) and MI-EPO (dotted loops) hearts revealed the increments of left ventricular stroke volume (LV-SV) in MI-EPO compared with MIC under baseline (upper panel) and dobutamine stress (middle panel) conditions. RV examinations (lower panel) displayed the reductions of right ventricular maximum pressure (RV-Pmax) and end-systolic pressure (RV-ESP) in MI-EPO compared with MIC under baseline conditions. *P< 0.05 MIC versus MI-EPO, **P< 0.01 MIC versus MI-EPO.

Mentions: Erythropoietin-α treatment enhanced systolic and diastolic properties of the infarcted LV both at baseline and under stress conditions. Hemodynamic changes are summarized in Table 1 (baseline) and Table 2 (dobutamine stress). EPO treatment produced a 53% increase in LV ejection fraction (LV-EF, P= 0.003, Fig. 1A), a 2-fold increase in LV stroke work and a 61% increase in LV stroke volume relative to MIC (P= 0.004, P= 0.019, Table 2) under stress conditions. Left ventricular peak rate of pressure rise (LV dp/dt max, Fig. 1A), a commonly used index of myocar-dial contractility, was significantly enhanced at baseline (P= 0.016) and under stress (P= 0.002) when compared with MIC. Moreover, we also observed a 24% increase in the peak rate of LV pressure decline (LV -dp/dt max) compared with MIC (Fig. 1A) under stress conditions, demonstrating enhanced relaxation in MI-EPO. Speed of relaxation in MIC was significantly lower both at baseline (P= 0.007) and under dobutamine stress (P = 0.045, Tables 1 and 2). Accordingly, LV relaxation time was longer (baseline: P= 0.003; stress: P= 0.022) in MIC than in MI-EPO hearts. Thus, EPO significantly improved contractility, reduced stiffness and improved elasticity of the LV. Representative single left ventricular heart beats are visualized in Fig. 1B. With respect to the performance of the right ventricle (RV), EPO improved significantly right ventricular loading conditions. RV maximum pressure (RV-Pmax) and RV end-systolic pressure (RV-ESP), whose elevations are consistent with pulmonary hypertension, were both reduced under baseline conditions in MI-EPO compared with MIC (P= 0.005, P= 0.003, Fig. 1A and B). However, RV dp/dt max did not significantly differ between the two groups (P= 0.199). MI-EPO hearts responded to dobutamine stress with a significant increase in heart rate (P= 0.019, Table 2). Taken together, these results demonstrate that direct administration of EPO improved both left and right ventricular performance.


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

Klopsch C, Furlani D, Gäbel R, Li W, Pittermann E, Ugurlucan M, Kundt G, Zingler C, Titze U, Wang W, Ong LL, Wagner K, Li RK, Ma N, Steinhoff G - J. Cell. Mol. Med. (2009)

Direct EPO injection restored cardiac functions 6 weeks after MI assessed by catheterization. (A) Left ventricular function (Sham n= 11, MIC n= 14, MI-EPO n= 11) at both baseline and stress conditions (left panel) as well as right ventricular function (Sham n= 5, MIC n= 8, MI-EPO n= 8) at baseline condition (right panel). (B) Representative single heart beat obtained from Sham (solid loops), MIC (dashed loops) and MI-EPO (dotted loops) hearts revealed the increments of left ventricular stroke volume (LV-SV) in MI-EPO compared with MIC under baseline (upper panel) and dobutamine stress (middle panel) conditions. RV examinations (lower panel) displayed the reductions of right ventricular maximum pressure (RV-Pmax) and end-systolic pressure (RV-ESP) in MI-EPO compared with MIC under baseline conditions. *P< 0.05 MIC versus MI-EPO, **P< 0.01 MIC versus MI-EPO.
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Related In: Results  -  Collection

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fig01: Direct EPO injection restored cardiac functions 6 weeks after MI assessed by catheterization. (A) Left ventricular function (Sham n= 11, MIC n= 14, MI-EPO n= 11) at both baseline and stress conditions (left panel) as well as right ventricular function (Sham n= 5, MIC n= 8, MI-EPO n= 8) at baseline condition (right panel). (B) Representative single heart beat obtained from Sham (solid loops), MIC (dashed loops) and MI-EPO (dotted loops) hearts revealed the increments of left ventricular stroke volume (LV-SV) in MI-EPO compared with MIC under baseline (upper panel) and dobutamine stress (middle panel) conditions. RV examinations (lower panel) displayed the reductions of right ventricular maximum pressure (RV-Pmax) and end-systolic pressure (RV-ESP) in MI-EPO compared with MIC under baseline conditions. *P< 0.05 MIC versus MI-EPO, **P< 0.01 MIC versus MI-EPO.
Mentions: Erythropoietin-α treatment enhanced systolic and diastolic properties of the infarcted LV both at baseline and under stress conditions. Hemodynamic changes are summarized in Table 1 (baseline) and Table 2 (dobutamine stress). EPO treatment produced a 53% increase in LV ejection fraction (LV-EF, P= 0.003, Fig. 1A), a 2-fold increase in LV stroke work and a 61% increase in LV stroke volume relative to MIC (P= 0.004, P= 0.019, Table 2) under stress conditions. Left ventricular peak rate of pressure rise (LV dp/dt max, Fig. 1A), a commonly used index of myocar-dial contractility, was significantly enhanced at baseline (P= 0.016) and under stress (P= 0.002) when compared with MIC. Moreover, we also observed a 24% increase in the peak rate of LV pressure decline (LV -dp/dt max) compared with MIC (Fig. 1A) under stress conditions, demonstrating enhanced relaxation in MI-EPO. Speed of relaxation in MIC was significantly lower both at baseline (P= 0.007) and under dobutamine stress (P = 0.045, Tables 1 and 2). Accordingly, LV relaxation time was longer (baseline: P= 0.003; stress: P= 0.022) in MIC than in MI-EPO hearts. Thus, EPO significantly improved contractility, reduced stiffness and improved elasticity of the LV. Representative single left ventricular heart beats are visualized in Fig. 1B. With respect to the performance of the right ventricle (RV), EPO improved significantly right ventricular loading conditions. RV maximum pressure (RV-Pmax) and RV end-systolic pressure (RV-ESP), whose elevations are consistent with pulmonary hypertension, were both reduced under baseline conditions in MI-EPO compared with MIC (P= 0.005, P= 0.003, Fig. 1A and B). However, RV dp/dt max did not significantly differ between the two groups (P= 0.199). MI-EPO hearts responded to dobutamine stress with a significant increase in heart rate (P= 0.019, Table 2). Taken together, these results demonstrate that direct administration of EPO improved both left and right ventricular performance.

Bottom Line: 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 mm2; n = 6-8, P < 0.001) than MIC hearts.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiac Surgery, University of Rostock, Germany.

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 mm2; 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.

Show MeSH
Related in: MedlinePlus