Erythropoietin and a nonerythropoietic peptide analog promote aortic endothelial cell repair under hypoxic conditions: role of nitric oxide

Heikal, Lamia; Ghezzi, Pietro; Mengozzi, Manuela; Stelmaszczuk, Blanka; Feelisch, Martin; Ferns, Gordon A.

doi:10.2147/hp.s104377

Cited by 18 publications

(15 citation statements)

References 40 publications

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“…Hypoxia was associated with a reduction in nitric oxide (NO) production. HBSP notably increased NO production, in a manner sensitive to NO synthase inhibition, under hypoxic conditions but not under normoxic conditions [43]. In summary, multiple studies proved the protective effect of HBSP on myocardial tissues and endothelial cells in the cardiovascular system following the injury caused by insufficient oxygen supply and implied that Akt pathway played a critical role in this process.…”

Section: In Cardiovascular Systemmentioning

confidence: 82%

“…In a study regarding the protection of HBSP on DCM, HBSP notably improved cardiac function, attenuated cardiac interstitial fibrosis, inhibited myocardial apoptosis, and ameliorated mitochondrial ultrastructure in mice with diabetic cardiomyopathy through an AMPK-dependent pathway [42]. HBSP promoted aortic endothelial cell repair under hypoxic conditions in a model of aortic endothelial injury, in which HBSP enhanced scratch closure by promoting cell migration and proliferation [43]. Furthermore, EPO protected bovine aortic endothelial cells from staurosporine-induced apoptosis under hypoxic conditions.…”

Section: In Cardiovascular Systemmentioning

confidence: 98%

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The Role of Erythropoietin-Derived Peptides in Tissue Protection

Zhang¹,

Yang²

2018

Polypeptide - New Insight Into Drug Discovery and Development

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Erythropoietin (EPO), recognized as a tissue protective agent, can trigger anti-inflammatory and anti-apoptotic processes to delimit injury and promote repair by the binding tissueprotective receptor. However, only at a high dosage can EPO exert tissue protective effects, which simultaneously elicits some severe erythropoiesis-related side effects. Thus, the structural modification of EPO for the prevention of side effects is undoubtedly required. This chapter reviewed the development from EPO to its peptide derivatives with tissue protective efficacy. We also discussed are the therapeutic effects and limitations of each peptide, signaling pathways involved and the benefits for translation.

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Section: In Cardiovascular Systemmentioning

confidence: 82%

Section: In Cardiovascular Systemmentioning

confidence: 98%

The Role of Erythropoietin-Derived Peptides in Tissue Protection

Zhang¹,

Yang²

2018

Polypeptide - New Insight Into Drug Discovery and Development

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“…HIF-1 is then able to interact with its coactivators and can dimerize with its constitutively expressed β-subunit [12]. Once stabilized, the HIF-1 protein can bind to the regulatory regions of its target genes, inducing their expression; these target genes include VEGF (vascular endothelial growth factor) [13], erythropoietin [14] and nitric oxide synthase (NOS) [15,16] and other proangiogenic factors such as PlGF (placental growth factor), or angiopoietins [12] (Figure 1).…”

Section: Consequences Of Hypoxiamentioning

confidence: 99%

Hypoxia, Angiogenesis and Atherogenesis

Heikal¹,

Ferns²

2017

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

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The balance between vascular oxygen supply and metabolic demand for oxygen within the vasculature is tightly regulated. An imbalance leads to hypoxia and a consequential cascade of cellular signals that attempt to offset the effects of hypoxia. Hypoxia is invariably associated with atherosclerosis, wound repair, inflammation and vascular disease.There is now substantial evidence that hypoxia plays an essential role in angiogenesis as well as plaque angiogenesis. It controls the metabolism, and responses of many of the cell types found within the developing plaque and whether the plaque will evolve into a stable or unstable phenotype. Hypoxia is characterized in molecular terms by the stabilization of hypoxia-inducible factor (HIF)-1α, a subunit of the heterodimeric nuclear transcriptional factor HIF-1 and a master regulator of oxygen homeostasis. The expression of HIF-1 is localized to perivascular tissues, inflammatory macrophages and smooth muscle cells where it regulates several genes that are important to vascular function including vascular endothelial growth factor, nitric oxide synthase, endothelin-1 and erythropoietin. This chapter summarizes the effects of hypoxia on the functions of cells involved in angiogenesis as well as atherogenesis (plaque angiogenesis) and the evidence for its potential importance from experimental models and clinical studies.

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“…EPO has been shown to be tissue-protective in models of ischaemic, traumatic and inflammatory injury [15]. Hypoxia enhances the reparative response of ECs to EPO [16,17]. This is likely to be mediated by hypoxia inducible factor (HIF)-1.…”

Section: Introductionmentioning

confidence: 99%

“…This is likely to be mediated by hypoxia inducible factor (HIF)-1. Dimethyloxalylglycine (DMOG) is a HIF-1α inducer and mimics conditions similar to hypoxia [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

3D Bioprinting of Novel Biocompatible Scaffolds for Endothelial Cell Repair

Heikal

Ferns

et al. 2019

Polymers

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The aim of this study was to develop and evaluate an optimized 3D bioprinting technology in order to fabricate novel scaffolds for the application of endothelial cell repair. Various biocompatible and biodegradable macroporous scaffolds (D = 10 mm) with interconnected pores (D = ~500 µm) were fabricated using a commercially available 3D bioprinter (r3bEL mini, SE3D, USA). The resolution of the printing layers was set at ~100 µm for all scaffolds. Various compositions of polylactic acid (PLA), polyethylene glycol (PEG) and pluronic F127 (F127) formulations were prepared and optimized to develop semi-solid viscous bioinks. Either dimethyloxalylglycine (DMOG) or erythroprotein (EPO) was used as a model drug and loaded in the viscous biocompatible ink formulations with a final concentration of 30% (w/w). The surface analysis of the bioinks via a spectroscopic analysis revealed a homogenous distribution of the forming materials throughout the surface, whereas SEM imaging of the scaffolds showed a smooth surface with homogenous macro-porous texture and precise pore size. The rheological and mechanical analyses showed optimum rheological and mechanical properties of each scaffold. As the drug, DMOG, is a HIF-1 inducer, its release from the scaffolds into PBS solution was measured indirectly using a bioassay for HIF-1α. This showed that the release of DMOG was sustained over 48 h. The release of DMOG was enough to cause a significant increase in HIF-1α levels in the bioassay, and when incubated with rat aortic endothelial cells (RAECs) for 2 h resulted in transcriptional activation of a HIF-1α target gene (VEGF). The optimum time for the increased expression of VEGF gene was approximately 30 min and was a 3-4-fold increase above baseline. This study provides a proof of concept, that a novel bioprinting platform can be exploited to develop biodegradable composite scaffolds for potential clinical applications in endothelial cell repair in cardiovascular disease (CVD), or in other conditions in which endothelial damage occurs.

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Erythropoietin and a nonerythropoietic peptide analog promote aortic endothelial cell repair under hypoxic conditions: role of nitric oxide

Cited by 18 publications

References 40 publications

The Role of Erythropoietin-Derived Peptides in Tissue Protection

The Role of Erythropoietin-Derived Peptides in Tissue Protection

Hypoxia, Angiogenesis and Atherogenesis

3D Bioprinting of Novel Biocompatible Scaffolds for Endothelial Cell Repair

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