Single high-dose intramyocardial administration of erythropoietin promotes early intracardiac proliferation, proves safety and restores cardiac performance after myocardial infarction in rats☆

Gäbel, Ralf; Furlani, Dario; Yerebakan, Can; Li, Wenzhong; Uğurlucan, Murat; Ma, Nan; Steinhoff, Gustav

doi:10.1510/icvts.2008.191916

Cited by 17 publications

(14 citation statements)

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“…While this study was only small and comes with all the limitations of a single‐centre study, the double‐blind, placebo‐controlled nature of the study at least encourages the design of larger randomized trials based on this protocol. In addition, the study supports experimental animal data demonstrating improved LV remodelling through epoetin‐β‐induced mobilization of functional endothelial progenitor cells 12,17…”

Section: Discussionsupporting

confidence: 81%

A pilot study of chronic, low-dose epoetin-β following percutaneous coronary intervention suggests safety, feasibility, and efficacy in patients with symptomatic ischaemic heart failure

Bergmann

Haufe

Knobelsdorff‐Brenkenhoff

et al. 2011

European Journal of Heart Failure

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AimsLow-dose epoetin-b improved neo-angiogenesis and cardiac regeneration in experimental models of ischaemic cardiomyopathy without raising haemoglobin. No clinical study has tested this approach to date. Methods and resultsWe performed a randomized, placebo-controlled, double-blind, single-centre study of 35 IU/kg body weight epoetin-b given subcutaneously once weekly for 6 months started within 3 weeks after successful percutaneous coronary intervention (PCI). Patients were included if they presented with a lesion within the proximal segment of the left anterior descending artery, the right coronary artery, or circumflex and had symptomatic heart failure. Patients with ST-segment elevation due to an acute myocardial infarct were excluded. The outcome variables were measured at baseline and at 6 months. Primary outcome measure was individual change in ejection fraction; secondary outcome was safety, change in N-terminal pro-brain natriuretic peptide, and peak VO 2 . Twenty-four patients completed the 6-month treatment course. No adverse event related to the treatment occurred. Low-dose epoetin-b following PCI significantly improved global ejection fraction as measured by echocardiography (EPO: DEF 5.2 + 2.0%, P ¼ 0.013; placebo: DEF 0.3 + 1.6%, P ¼ 0.851; P ¼ 0.019 for the inter-group difference) and cardiac magnetic resonance (EPO: DEF 3.1 + 1.6%, P ¼ 0.124; placebo: 21.9 + 1.2%, P ¼ 0.167; P ¼ 0.042 for the inter-group difference). N-terminal pro-brain natriuretic peptide levels decreased in both groups without significant inter-group differences. Peak VO 2 levels increased significantly by 3.9 + 1.1% (P , 0.05) in the EPO group, whereas in the placebo group the increase did not reach statistical significance (Dpeak VO 2 3.0 + 1.6, P ¼ ns). No significant difference regarding peak VO 2 was observed between the EPO and placebo groups. ConclusionsLow-dose epoetin-b treatment following PCI is safe and feasible, and has possible beneficial effects on global ejection fraction and measures of exercise capacity. Extended low-dose epoetin-b treatment warrants further mechanistic studies as well as larger clinical trials.

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Section: Discussionsupporting

confidence: 81%

A pilot study of chronic, low-dose epoetin-β following percutaneous coronary intervention suggests safety, feasibility, and efficacy in patients with symptomatic ischaemic heart failure

Bergmann

Haufe

Knobelsdorff‐Brenkenhoff

et al. 2011

European Journal of Heart Failure

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“…At the cellular level, we observed that Epo induced EPOR pos cell proliferation and EMCs accumulation in ischemic myocardium. In line with our data, intracardiac injections of Epo in infarcted rat myocardium enhanced proliferation of interstitial cells . Ten weeks post‐MI, we found a higher number of intracardiac EMCs located in between well‐preserved myocytes in the scar of Epo‐treated mice.…”

Section: Discussionsupporting

confidence: 91%

Erythropoietin Responsive Cardiomyogenic Cells Contribute to Heart Repair Post Myocardial Infarction

et al. 2014

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The role of erythropoietin (Epo) in myocardial repair after infarction remains inconclusive. We observed high Epo receptor (EPOR) expression in cardiac progenitor cells (CPCs). Therefore, we aimed to characterize these cells and elucidate their contribution to myocardial regeneration on Epo stimulation. High EPOR expression was detected during murine embryonic heart development followed by a marked decrease until adulthood. EPOR-positive cells in the adult heart were identified in a CPC-enriched cell population and showed coexpression of stem, mesenchymal, endothelial, and cardiomyogenic cell markers. We focused on the population coexpressing early (TBX5, NKX2.5) and definitive (myosin heavy chain [MHC], cardiac Troponin T [cTNT]) cardiomyocyte markers. Epo increased their proliferation and thus were designated as Eporesponsive MHC expressing cells (EMCs). In vitro, EMCs proliferated and partially differentiated toward cardiomyocyte-like cells. Repetitive Epo administration in mice with myocardial infarction (cumulative dose 4 IU/g) resulted in an increase in cardiac EMCs and cTNT-positive cells in the infarcted area. This was further accompanied by a significant preservation of cardiac function when compared with control mice. Our study characterized an EPO-responsive MHCexpressing cell population in the adult heart. Repetitive, moderate-dose Epo treatment enhanced the proliferation of EMCs resulting in preservation of post-ischemic cardiac function.

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“…These foci may be regeneration sites repopulated with CPCs. Since treatment with Dox was reported to induce CPC death, AN-7 protection of the c-Kit positive cells is likely to preserve the CPCs and therefore the cardio-regeneration capacity [48], [50], [51]. Angelis et al suggested that Dox-induced depletion of the CPC pool within the myocardium contributes to the dramatic manifestation of heart failure in animal models and humans due to the diminished regenerative capacity of their hearts [51].…”

Section: Discussionmentioning

confidence: 99%

Disparate Impact of Butyroyloxymethyl Diethylphosphate (AN-7), a Histone Deacetylase Inhibitor, and Doxorubicin in Mice Bearing a Mammary Tumor

et al. 2012

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The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) synergizes the cytotoxic effect of doxorubicin (Dox) and anti-HER2 on mammary carcinoma cells while protecting normal cells against their insults. This study investigated the concomitant changes occurring in heart tissue and tumors of mice bearing a subcutaneous 4T1 mammary tumor following treatment with AN-7, Dox, or their combination. Dox or AN-7 alone led to inhibition of both tumor growth and lung metastases, whereas their combination significantly increased their anticancer efficacy and attenuated Dox- toxicity. Molecular analysis revealed that treatment with Dox, AN-7, and to a greater degree, AN-7 together with Dox increased tumor levels of γH2AX, the marker for DNA double-strand breaks and decreased the expression of Rad51, a protein needed for DNA repair. These events culminated in increased apoptosis, manifested by the appearance of cytochrome-c in the cytosol. In the myocardium, Dox-induced cardiomyopathy was associated with an increase in γH2AX expression and a reduction in Rad51 and MRE11 expression and increased apoptosis. The addition of AN-7 to the Dox treatment protected the heart from Dox insults as was manifested by a decrease in γH2AX levels, an increase in Rad51 and MRE11 expression, and a diminution of cytochrome-c release. Tumor fibrosis was high in untreated mice but diminished in Dox- and AN-7-treated mice and was almost abrogated in AN-7+Dox-treated mice. By contrast, in the myocardium, Dox alone induced a dramatic increase in fibrosis, and AN7+Dox attenuated it. The high expression levels of c-Kit, Ki-67, c-Myc, lo-FGF, and VEGF in 4T1 tumors were significantly reduced by Dox or AN-7 and further attenuated by AN-7+Dox. In the myocardium, Dox suppressed these markers, whereas AN-7+Dox restored their expression. In conclusion, the combination of AN-7 and Dox results in two beneficial effects, improved anticancer efficacy and cardioprotection.

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Single high-dose intramyocardial administration of erythropoietin promotes early intracardiac proliferation, proves safety and restores cardiac performance after myocardial infarction in rats☆

Cited by 17 publications

References 14 publications

A pilot study of chronic, low-dose epoetin-β following percutaneous coronary intervention suggests safety, feasibility, and efficacy in patients with symptomatic ischaemic heart failure

A pilot study of chronic, low-dose epoetin-β following percutaneous coronary intervention suggests safety, feasibility, and efficacy in patients with symptomatic ischaemic heart failure

Erythropoietin Responsive Cardiomyogenic Cells Contribute to Heart Repair Post Myocardial Infarction

Disparate Impact of Butyroyloxymethyl Diethylphosphate (AN-7), a Histone Deacetylase Inhibitor, and Doxorubicin in Mice Bearing a Mammary Tumor

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