Erythropoietin Triggers a Signaling Pathway in Endothelial Cells and Increases the Thrombogenicity of their Extracellular Matrices In Vitro

Fusté, Berta; Serradell, Mireia; Escolar, Ginés; Cases, Aleix; Mazzara, Roberto; Castillo, Rafael; Ordinas, Antonio; Díaz‐Ricart, Maribel

doi:10.1055/s-0037-1613275

Cited by 79 publications

(48 citation statements)

References 38 publications

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“…Even a single exposure of normal humans to EPO causes a dose-dependent increase in E-selectin within 2 days, which is consistent with significant endothelial cell activation (41). Similar responses have also been documented for other markers associated with thrombosis, e.g., P-selectin, and in vitro studies confirm direct and rapid prothrombotic effects of EPO on the endothelium (42). Clearly, an increased potential for thrombosis is not desirable in vascular occlusive myocardial disease.…”

Section: Discussionsupporting

confidence: 63%

A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia–reperfusion injury

Fiordaliso

Chimenti

Staszewsky

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

201

134

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The cytokine erythropoietin (EPO) protects the heart from ischemic injury, in part by preventing apoptosis. However, EPO administration can also raise the hemoglobin concentration, which, by increasing oxygen delivery, confounds assignment of cause and effect. The availability of EPO analogs that do not bind to the dimeric EPO receptor and lack erythropoietic activity, e.g., carbamylated EPO (CEPO), provides an opportunity to determine whether EPO possesses direct cardioprotective activity. In vivo, cardiomyocyte loss after experimental myocardial infarction (MI) of rats (40 min of occlusion with reperfusion) was reduced from Ϸ57% in MI-control to Ϸ45% in animals that were administered CEPO daily for 1 week (50 g͞kg of body weight s.c.) with the first dose administered intravenously 5 min before reperfusion. CEPO did not increase the hematocrit, yet it prevented increases in left ventricular (LV) end-diastolic pressure, reduced LV wall stress in systole and diastole, and improved LV response to dobutamine infusion compared with vehicle-treated animals. In agreement with the cardioprotective effect observed in vivo, staurosporineinduced apoptosis of adult rat or mouse cardiomyocytes in vitro was also significantly attenuated (Ϸ35%) by CEPO, which is comparable with the effect of EPO. These data indicate that prevention of cardiomyocyte apoptosis, in the absence of an increase in hemoglobin concentration, explains EPO's cardioprotection. Nonerythropoietic derivatives such as CEPO, devoid of the undesirable effects of EPO, e.g., thrombogenesis, could represent safer and more effective alternatives for treatment of cardiovascular diseases, such as MI and heart failure. Furthermore, these findings expand the activity spectrum of CEPO to tissues outside the nervous system. apoptosis ͉ cardioprotection ͉ cytokine ͉ tissue injury E rythropoietin (EPO) protects the brain and the spinal cord from ischemic and traumatic injury (1, 2), the peripheral nerve from diabetic damage (3), the kidney from ischemic (4, 5) or toxic insults (6), and the heart from acute ischemia, either permanent (7-9) or with reperfusion (10). Current data suggest that the observed protective effects of EPO depend on an antiapoptotic effect of this cytokine (7, 10). In the brain, EPO also greatly reduces the inflammatory response after ischemiareperfusion (11). It is notable that in several acute models, e.g., brain ischemia, a single dose of EPO that does not increase the Hb concentration nevertheless confers neuroprotection. However, in other in vivo injury models, including cardiac ischemia with reperfusion and diabetic neuropathy, injury develops gradually, and multiple doses of EPO appear superior but also increase the Hb concentration. The possibility that part of the benefit obtained with EPO in these models may depend on the increased oxygen-carrying capacity of the blood cannot be excluded. However, cardiac protection has clearly been demonstrated after only a single dose (8, 10) when evaluated 1-3 days after infarction before any increase i...

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Section: Discussionsupporting

confidence: 63%

A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia–reperfusion injury

Fiordaliso

Chimenti

Staszewsky

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

201

134

View full text Add to dashboard Cite

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“…The precise mechanism by which EPO induces a thrombotic event, remains unclear. Prothrombotic effect of EPO might associated with abruptly increased hematocrit values, enhanced platelet production or reactivity, stimulation of endothelial cells or reduced coagulation inhibitors (9,10).…”

Section: Discussionmentioning

confidence: 99%

Acute coronary syndrome with intraventricular thrombus after using erythropoietin

Kurtul¹,

Duran²,

Uysal³

et al. 2013

Anadolu Kardiyol Derg

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“…Increased circulating vWF from activated endothelial cells and/or PLTs (Rondaij et al 2006) has been documented in diverse patient populations with thrombotic complications (Tousoulis et al 2007;Adachi et al 2006;Mina, Favaloro, and Koutts 2007) and correlated with clinical deterioration of acute stroke patients (Barber et al 2004). While increased expression of vWF has been detected in vitro on endothelial cells and PLTs incubated with rHu-EPO (Fuste et al 2002), increased circulating vWF was not detected in chronic renal failure patients (Pawlak, Pawlak, and Mysliwiec 2007;Christensson, Danielson, and Lethagen 2001) or healthy human volunteers (Heinisch et al 2012) administered chronic or an acute dose of rHu-EPO, respectively. This suggests the early increased vWF in AMG 114 high-dose rats was most likely indirectly related to AMG 114 administration and not due to direct activation of endothelial cells and/or PLTs.…”

Section: Discussionmentioning

confidence: 99%

Cytokines Associated with Increased Erythropoiesis in Sprague-Dawley Rats Administered a Novel Hyperglycosylated Analog of Recombinant Human Erythropoietin

Andrews

Hamadeh

et al. 2013

Toxicol Pathol

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We previously reported an increased incidence of thrombotic toxicities in Sprague-Dawley rats administered the highest dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114) for 1 month as not solely dependent on high hematocrit (HCT). Thereafter, we identified increased erythropoiesis as a prothrombotic risk factor increased in the AMG 114 high-dose group with thrombotic toxicities, compared to a low-dose group with no toxicities but similar HCT. Here, we identified pleiotropic cytokines as prothrombotic factors associated with AMG 114 dose level. Before a high HCT was achieved, rats in the AMG 114 high, but not the low-dose group, had imbalanced hemostasis (increased von Willebrand factor and prothrombin time, decreased antithrombin III) coexistent with cytokines implicated in thrombosis: monocyte chemotactic protein 1 (MCP-1), MCP-3, tissue inhibitor of metalloproteinases 1, macrophage inhibitory protein-2, oncostatin M, T-cell-specific protein, stem cell factor, vascular endothelial growth factor, and interleukin-11. While no unique pathway to erythropoiesis stimulating agent-related thrombosis was identified, cytokines associated with increased erythropoiesis contributed to a prothrombotic intravascular environment in the AMG 114 highdose group, but not in lower dose groups with a similar high HCT.

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Erythropoietin Triggers a Signaling Pathway in Endothelial Cells and Increases the Thrombogenicity of their Extracellular Matrices In Vitro

Cited by 79 publications

References 38 publications

A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia–reperfusion injury

A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia–reperfusion injury

Acute coronary syndrome with intraventricular thrombus after using erythropoietin

Cytokines Associated with Increased Erythropoiesis in Sprague-Dawley Rats Administered a Novel Hyperglycosylated Analog of Recombinant Human Erythropoietin

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