Transcriptional Regulation of Endothelin-1 by Erythropoietin in Endothelial Cells

Liefeldt, Lutz; Schmidt‐Ott, Kai M.; Orzechowski, Hans‐Dieter; Distler, A.; Paul, Martin

doi:10.1097/00005344-199800001-00132

Cited by 14 publications

(9 citation statements)

References 6 publications

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“…11 Increased prepro ET-1 mRNA has also been observed in cultured bovine aortic endothelial cells and human umbilical vein endothelial cells stimulated with pharmacological doses of rHuEPO. 12 We have been unable to demonstrate any change in urinary ET-1 concentrations in cortisol treated subjects. 13 However, the described effects of EPO on vascular reactivity may be important in cortisol treated subjects in mediating a shift of vascular reactivity away from dilator substance such as NO and in favour of constrictor substances such as endothelin.…”

Section: Discussionmentioning

confidence: 57%

Role of erythropoietin in cortisol-induced hypertension

2000

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The mechanism of cortisol-induced hypertension remains unknown. We investigated a possible role of erythropoietin (EPO) as a mediator of hypertension in healthy male subjects treated with cortisol. In Study 1, blood pressure (BP) and serum EPO concentrations were measured on alternate days in nine subjects treated with 80 mg of cortisol per day for 5 days. In Study 2 the same parameters were measured in eight subjects randomised to cortisol (80 mg/day) or placebo and 10 subjects randomised to cortisol (200 mg/day) or placebo for 5 days. In Study 1, cortisol caused a significant increase in systolic BP (SBP) (115 ؎ 2 vs 126 ؎ 2 mm Hg, control vs day 5, P Ͻ 0.001) and serum EPO

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Section: Discussionmentioning

confidence: 57%

Role of erythropoietin in cortisol-induced hypertension

2000

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“…For example, EPO could provide additional protection to cardiomyocytes via crosstalking or by paracrine release of other cardioprotective factors. Indeed, EPO was reported to induce endothelial cells to release endothelin-1 (Liefeldt et al, 1998), which is known to inhibit apoptosis in various types of cells, including cardiomyocytes. Clearly, more studies will be required to determine the optimal timing and dosing levels required to maximize the benefit of EPO in treating DOX-induced cardiac injury and dysfunction and to assess other potential cardioprotective mechanisms of EPO against DOX.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin Protects against Doxorubicin-Induced Cardiomyopathy via a Phosphatidylinositol 3-Kinase-Dependent Pathway

Kim

Oudit²,

Backx³

2007

J Pharmacol Exp Ther

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Doxorubicin (DOX) is an effective antineoplastic agent whose use has been limited by its cardiotoxic side effects. Recent studies have established that erythropoietin (EPO), a cytokine essential for red blood cell production, protects against ischemic injury in the heart and other organs. The purpose of this study was to assess whether EPO protects the heart against cardiotoxicity induced by DOX. We found that DOX-induced apoptosis and impaired heart function in mice were largely prevented by EPO administration. To investigate the mechanism of protection by EPO, cultured neonatal mouse ventricular myocytes were treated with EPO at therapeutic levels (i.e., 1 U/ml), before application of DOX (0.1-1.0 M). EPO protected against DOX-induced cardiomyocyte death (by Ϸ50%) and apoptosis assessed by annexin-V labeling, DNA fragmentation, and caspase-3 activity. DOX-mediated increases in reactive oxygen species, which trigger cardiotoxicity, were also reversed by preconditioning with EPO. These functional effects of EPO correlated with increased Akt/protein kinase B (ϳ2-fold) and glycogen synthase kinase 3 (GSK-3; ϳ1.3-fold) phosphorylations, suggesting protection by EPO was mediated by phosphatidylinositol 3-kinase activation. Indeed, preventing Akt and GSK-3␤ phosphorylations by phosphatidylinositol 3-kinase (PI3K) inhibition abolished protection by EPO against cardiomyocyte loss, apoptosis, and oxidative stress. Thus, pretreatment with therapeutic levels of EPO can protect the myocardium against DOX-induced impaired heart function and cardiomyocyte apoptosis by activating PI3K-Akt cell survival pathways.Although the anthracycline antibiotic doxorubicin (DOX) has been used effectively to treat a broad range of human malignancies for decades, its clinical usage and efficacy are limited by side effects, especially cardiomyopathy and heart failure (Gewirtz, 1999). The mechanism for the cardiac toxicity associated with DOX treatment remains unclear. DOXinduced cardiomyopathy has been linked to apoptosis and DNA damage, free radical formation, and alterations of calcium metabolism (Takemura and Fujiwara, 2007). Recent studies showed that the programmed cardiomyocyte death induced by DOX was related to elevated reactive oxygen species, mitochondrial impairment (Takemura and Fujiwara, 2007), Fas-mediated pathway activation (Nitobe et al., 2003), and ceramide generation (Delpy et al., 1999).Clearly, preventing cardiomyopathy could increase the use and enhance the efficacy of DOX. In this regard, the cytokine erythropoietin (EPO), which stimulates both the production and maturation of red blood cells, has been shown to be cytoprotective against ischemic injury in the heart and other organs (Chong et al., 2002b;Parsa et al., 2003). The effects of EPO have been linked to its ability to reduce apoptosis in neurons (Chong et al., 2002b), vascular smooth muscle cells (Akimoto et al., 2000), vascular endothelial cells (Chong et al., 2002a), and cardiomyocytes (Parsa et al., 2003). Due to its effects on erythropoiesis, EPO is...

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“…First, erythropoietin receptor exists in endothelial cells (10), and rHuEPO increases the release of ET-1 from endothelial cells (11,12) as well as the expression of ET-1 mRNA in the endothelial cells (13). However, other investigators did not show the increase in ET-1 by erythropoietin (14).…”

Section: Discussionmentioning

confidence: 99%

Blood Pressure Response to Erythropoietin Injection in Hemodialysis and Predialysis Patients

et al. 2004

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lin-1 (ET-1) (7). However, it is not well established whether rHuEPO increases blood pressure via ET-1 in patients on hemodialysis.Patients with chronic renal failure (CRF) and renal anemia are also treated with rHuEPO before the initiation of hemodialysis. In chronic renal failure patients, blood pressure often increases with the progression of renal failure via salt retention. Even though it has been reported that about 20% of predialysis CRF patients show an increase in blood pressure with rHuEPO therapy (8, 9), it is difficult to distinguish the erythropoietin-induced hypertension from the blood pressure increase associated with the progression of renal failure. In this study, we investigated the effect of a single injection of rHuEPO on blood pressure and ET-1 in patients receiving hemodialysis and in predialysis chronic renal failure patients.

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Transcriptional Regulation of Endothelin-1 by Erythropoietin in Endothelial Cells

Cited by 14 publications

References 6 publications

Role of erythropoietin in cortisol-induced hypertension

Role of erythropoietin in cortisol-induced hypertension

Erythropoietin Protects against Doxorubicin-Induced Cardiomyopathy via a Phosphatidylinositol 3-Kinase-Dependent Pathway

Blood Pressure Response to Erythropoietin Injection in Hemodialysis and Predialysis Patients

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