Erythropoietin Attenuates the Development of Experimental Autoimmune Myocarditis

Hirose, Seiyu; Takahashi, Masafumi; Ogawa, Ryo; Morimoto, Hajime; Izawa, Atsushi; Sato, Hajime; Ise, Hirohiko; Hongo, Minoru; Ikeda, Uichi

doi:10.1007/s10557-007-6005-7

Cited by 16 publications

(14 citation statements)

References 41 publications

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“…41 In contrast to their findings, we could not confirm markedly reduced absolute numbers of degranulated cardiac mast cells in allografts harvested from Epotreated recipients. We may thus hypothesize that Epo exerts a more qualitative rather than quantitative effect on mast cell degranulation during myocardial I/R injury in cardiac allografts.…”

Section: Discussioncontrasting

confidence: 99%

Erythropoietin inhibits post-ischemic leukocyte adhesion but does not affect rejection in murine cardiac allografts

Schramm

Kirsch

Schäfers

et al. 2010

The Journal of Heart and Lung Transplantation

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Section: Discussioncontrasting

confidence: 99%

Erythropoietin inhibits post-ischemic leukocyte adhesion but does not affect rejection in murine cardiac allografts

Schramm

Kirsch

Schäfers

et al. 2010

The Journal of Heart and Lung Transplantation

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“…To investigate whether EPO affects responses of inflammation and wound healing that may have an impact on LV remodeling after MI (16,17), we examined macrophage infiltration and myofibroblast accumulation in the ischemic area after MI by immunohistochemical staining. The number of Mac3-positive macrophages was markedly decreased by EPO treatment 14 days after MI (Supplemental Figure 1A; supplemental material available with this article; doi:10.1172/ JCI39896DS1).…”

Section: Introductionmentioning

confidence: 99%

Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice

Ueda¹,

Takano²,

Niitsuma³

et al. 2010

J. Clin. Invest.

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Erythropoietin reportedly has beneficial effects on the heart after myocardial infarction, but the underlying mechanisms of these effects are unknown. We here demonstrate that sonic hedgehog is a critical mediator of erythropoietin-induced cardioprotection in mice. Treatment of mice with erythropoietin inhibited left ventricular remodeling and improved cardiac function after myocardial infarction, independent of erythropoiesis and the mobilization of bone marrow-derived cells. Erythropoietin prevented cardiomyocyte apoptosis and increased the number of capillaries and mature vessels in infarcted hearts by upregulating the expression of angiogenic cytokines such as VEGF and angiopoietin-1 in cardiomyocytes. Erythropoietin also increased the expression of sonic hedgehog in cardiomyocytes, and inhibition of sonic hedgehog signaling suppressed the erythropoietin-induced increase in angiogenic cytokine expression. Furthermore, the beneficial effects of erythropoietin on infarcted hearts were abolished by cardiomyocyte-specific deletion of sonic hedgehog. These results suggest that erythropoietin protects the heart after myocardial infarction by inducing angiogenesis through sonic hedgehog signaling.

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“…EPO therapy reduced the clinical expression of murine experimental autoimmune encephalomyelitis, 6 with associated reduction in effector T-cell (Teff) proliferation, expansion of regulatory T cells (Tregs), and inhibition of dendritic cell (DC) function. 7 A detailed understanding of how EPO alters murine T-cell function remains obscure, and whether and how EPO impacts human alloreactive T-cell immunity have not been carefully studied.…”

mentioning

confidence: 99%

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

Cravedi¹,

Manrique²,

Hanlon

et al. 2014

Journal of the American Society of Nephrology

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Correction of anemia with erythropoietin (EPO) is associated with improved kidney transplant outcomes. Emerging evidence, predominantly from animal models, indicates that these observations may be erythropoiesis-independent and that EPO exhibits immunosuppressive properties. We examined the effects of EPO on human T-cell alloimmunity by first documenting that CD4 + and CD8 + T cells express EPO receptor (EPO-R) on their surfaces. In mixed lymphocyte reactions, EPO induced a dose-dependent decrease in allogeneic CD4 + T-cell proliferation (EPO 1000 U/ml: 44.6%622.9% of vehicle, P,0.05; 2000 U/ml: 11.1%64% of vehicle, P,0.001) without inducing cell death. The effects required signals transmitted directly through the EPO-R expressed on T cells, resulting in diminished Th1 differentiation without effects on regulatory T-cell induction. Mechanistic studies revealed that EPO prevented IL-2-induced proliferation by uncoupling IL-2 receptor signaling, inhibiting phosphorylation of the intracellular intermediaries AKT and extracellular signal-regulated kinase that are known to mediate T-cell expansion. EPO treatment reduced expansion of human naïve CD4 + T cells after adoptive transfer into NOD scid gc null mouse recipients, verifying the effects in vivo. Although activated T cells expressed CD131, an alternative EPO receptor, addition of a specific CD131 agonist peptide, ARA290, did not alter T-cell proliferation or cytokine production. Our findings link EPO-R signaling on T cells to inhibition of T-cell immunity, providing one mechanism that could explain the observed protective effects of EPO in kidney transplant recipients. The anemia that commonly occurs in kidney transplant recipients has been hypothesized to contribute to chronic allograft injury, in part by limiting oxygen delivery to the tubulointersitium and as a consequence, enabling fibrogenesis. 1 In support of a link between anemia and kidney allograft injury, results of a 2012 randomized controlled study of erythropoietin (EPO) therapy after transplantation showed that targeting hemoglobin values to a normal range of $13 g/dl slowed progression of chronic allograft nephropathy and prolonged graft survival compared with partial correction of anemia. 2 Although the above-cited clinical study and selected studies in rodents indicate correlations between EPO-induced increases in hematocrit and reduced tubulointerstitial damage as well as preserved renal tubular cells and improved kidney function, 3 direct evidence linking EPO-induced erythropoiesis to better transplant outcomes is lacking. In fact, experiments performed in a fully mismatched rat kidney transplant model showed that EPO, but not the correction of anemia by blood transusion, limits chronic allograft injury, 4,5 supporting the conclusion that the transplant-protective effects of EPO do not require an EPO-induced increase in hematocrit. Among potential alternative mechanisms, emerging evidence from animal models suggests that

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Erythropoietin Attenuates the Development of Experimental Autoimmune Myocarditis

Cited by 16 publications

References 41 publications

Erythropoietin inhibits post-ischemic leukocyte adhesion but does not affect rejection in murine cardiac allografts

Erythropoietin inhibits post-ischemic leukocyte adhesion but does not affect rejection in murine cardiac allografts

Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

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