Erythropoietin Enhances Neovascularization of Ischemic Myocardium and Improves Left Ventricular Dysfunction After Myocardial Infarction in Dogs

Hirata, Akio; Minamino, Tetsuo; Asanuma, Hiroshi; Fujita, Masashi; Wakeno, Masakatsu; Myoishi, Masafumi; Tsukamoto, Osamu; Okada, Kenichiro; Koyama, Hidekazu; Komamura, Kazuo; Takashima, Seiji; Shinozaki, Yoshiro; Mori, Hiromu; Shiraga, Masamichi; Kitakaze, Masafumi; Hori, Masatsugu

doi:10.1016/j.jacc.2006.04.008

Cited by 115 publications

(78 citation statements)

References 29 publications

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“…Although cardiomyocyte proliferation after ischaemic injury seems limited, the formation of new vessels in the noninfarcted part of the ventricle could lead to an improvement of function and attenuation of ventricular remodelling [27,28]. Evidence is accumulating to suggest that EPO exerts potent pleiotropic effects on the myocardium in the setting of acute myocardial infarction and chronic heart failure as well [2,[5][6][7][8][9][10]29]. Therefore, in addition to its acute protective effects, EPO might evolve as a standard "cardioregenerative" therapy in the setting of chronic myocardial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, EPO improves cardiac function in experimental models of chronic myocardial dysfunction, which is consistently associated with improved microvascularisation of the myocardium [5][6][7][8][9][10]. The neovascularisation by EPO is associated with marked mobilisation and vascular incorporation of endothelial progenitor cells (EPC) [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Low‐dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

Lipšic

Westenbrink

Meer

et al. 2008

European J of Heart Fail

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Background: Erythropoietin (EPO) may improve cardiac function and induce neovascularisation in experimental models of chronic heart failure (CHF). However, the increased haematocrit associated with EPO treatment might exert concomitant deleterious effects. Aim: To investigate the haematocrit independent effects of EPO on cardiac function. Methods and results: Rats underwent permanent coronary artery ligation to induce myocardial infarction (MI) or sham surgery. Three weeks after MI, rats were randomly allocated to treatment with vehicle (MI) or the long-acting EPO analogue darbepoetin alfa administered in a high (40 μg/kg/3 weeks, MI-EPO-high) or a low-dose (0.4 μg/kg/3 weeks, MI-EPO-low). After 9 weeks, haemodynamic parameters, myocardial histology and Myosin Heavy Chain (MHC) isoforms were determined. High-dose EPO resulted in a significant increase in haematocrit (p b 0.01) while low-dose EPO had no effect on haematocrit levels. EPO significantly improved cardiac function in both EPO groups, reflected by increased left ventricular (LV)-developed pressure and improved contractility (dP/dt max ) and relaxation (dP/dt min ) indices of the LV at 9-weeks (all p b 0.05 compared to MI). The improved cardiac function was associated with increased capillary growth (38% in MI-EPO-high (p b 0.01) and 27% in MI-EPO-low (p b 0.05)) and an attenuated switch to slow β-MHC isoforms in both EPO groups. Conclusions: EPO improves cardiac function and induces neovascularisation at a dose that does not increase haematocrit, thereby circumventing the possible deleterious effects of increased erythropoiesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low‐dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

Lipšic

Westenbrink

Meer

et al. 2008

European J of Heart Fail

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show abstract

“…This result may be in line with previous reports by others demonstrating that STAT3 is required for VEGF upregulation and resultant capillary growth in the heart, 26 -28 that the disruption of coordinated cardiac hypertrophy and endogenous VEGFinduced angiogenesis accelerates the development of heart failure in hypertrophied hearts, 6,7 and that administration of Epo promotes coronary angiogenesis in animal models of myocardial infarction. 18,29 The deletion of the endogenous Epo-EpoR system in nonhematopoietic cells in mice with LV pressure overload may impair STAT3 activation, VEGF upregulation, and capillary growth, resulting in heart failure. The impaired capillary growth in EpoR Ϫ/Ϫ rescued mice with TAC may result in failure to supply sufficient blood flow to hypertrophied cardiomyocytes.…”

Section: Epormentioning

confidence: 99%

Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload–Induced Left Ventricular Dysfunction in Mice

et al. 2007

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Background— Erythropoietin (Epo) receptors (EpoRs) are expressed in the heart. We have recently demonstrated that the endogenous Epo-EpoR system plays an important protective role in myocardial ischemia in mice and humans. In the present study, we tested our hypothesis that the endogenous Epo-EpoR system in nonhematopoietic cells also plays a protective role against pressure overload–induced cardiac dysfunction in vivo. Methods and Results— Transgene-rescued EpoR-null mutant mice ( EpoR −/− rescued ) that express EpoR exclusively in the hematopoietic cells were subjected to transverse aortic constriction (TAC). At 1 week after TAC, left ventricular weight and lung weight were significantly increased in EpoR −/− rescued mice compared with wild-type mice, although the fibrotic area was comparably increased after TAC in the 2 genotypes. In the EpoR −/− rescued mice with TAC, left ventricular end-diastolic diameter was significantly increased, left ventricular fractional shortening was significantly decreased, and survival rate was significantly decreased compared with wild-type mice with TAC. Phosphorylation of STAT3 at 5 hours and 1 week after TAC and that of p38 at 5 hours after TAC were significantly increased in wild-type mice but not in EpoR −/− rescued mice. Vascular endothelial growth factor protein expression and capillary density in left ventricular myocardium were significantly decreased in EpoR −/− rescued mice with TAC compared with wild-type mice with TAC. Conclusions— These results suggest that the endogenous Epo-EpoR system in the nonhematopoietic cells plays an important protective role against pressure overload–induced cardiac dysfunction in vivo.

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“…29,30 EPO also protects the myocardium in a rat myocarditis model. 31 We then undertook clinical trials of EPO administration for patients with acute myocardial infarction (AMI) to observe its safety and efficacy: the EPO/AMI-1 study, 32 and under the results of this trial, we began a three-arm, double-blind clinical trial of EPO administration for 600 patients with AMI: the EPO/AMI-2 study.…”

Section: Discussionmentioning

confidence: 98%

A novel synthetic derivative of human erythropoietin designed to bind to glycosaminoglycans

Matsushima¹,

Toba²,

Hanawa³

et al. 2012

Drug Delivery

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Erythropoietin Enhances Neovascularization of Ischemic Myocardium and Improves Left Ventricular Dysfunction After Myocardial Infarction in Dogs

Abstract: In addition to its acute infarct size-limiting effect, EPO enhances neovascularization, likely via EPC mobilization, and improves cardiac dysfunction in the chronic phase, although it has time-window limitations.

Cited by 115 publications

References 29 publications

Low‐dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

Low‐dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload–Induced Left Ventricular Dysfunction in Mice

A novel synthetic derivative of human erythropoietin designed to bind to glycosaminoglycans

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