Epo deficiency alters cardiac adaptation to chronic hypoxia

Hasnaoui-Saadani, Raja El; Marchant, Dominique; Pichon, Aurélien; Escoubet, Brigitte; Pezet, Mylène; Hilfiker‐Kleiner, Denise; Hoch, Mélanie; Pham, Isabelle; Quidu, Patricia; Voituron, Nicolas; Journé, Clément; Richalet, Jean‐Paul; Favret, Fabrice

doi:10.1016/j.resp.2013.01.003

Cited by 19 publications

(24 citation statements)

References 32 publications

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“…As previously described [55], chronic hypoxia led to the activation of HIF-1α/VEGF pathway in the heart of adult wild-type mice most probably responsible for their enhanced myocardial angiogenesis. Also we demonstrated the activation of cardioprotective pathways, involving HIF-1α and Epo, as suggested by the increase of EpoR expression and P-STAT-5/STAT-5 ratio [47]. Furthermore, we could not exclude a cardiac metabolic gene remodeling since temporal changes in glucose metabolic genes in response to moderate hypobaric hypoxia [56] have been demonstrated.…”

Section: Heart Under Chronic Hypoxiamentioning

confidence: 78%

“…Indeed, we evidenced that Epo deiciency activated cerebral hypoxic mechanisms through HIF activation that promote angiogenesis [23]. In addition, the JAK/STAT signaling pathway mediated by the Epo/EpoR complex seems to be activated by chronic anemia [23,47] and could promote neuroprotection and cell proliferation [71]. Furthermore, more recent results showed that nNOS is speciically protective during anemia [57].…”

Section: Brain Under Chronic Anemiamentioning

confidence: 89%

“…Moreover, cardiac output was not afected by chronic hypoxia alone and oxygen delivery was maintained. In addition, hypoxic wild-type mice responded by increasing plasma Epo and blood hemoglobin, resulting in a rise in oxygen-carrying capacity [47].…”

Section: Heart Under Chronic Hypoxiamentioning

confidence: 99%

“…Through speciic binding to its receptor EpoR, Epo triggers intracellular signaling events that depend on the activation of Jak2 tyrosine kinase [51]. The exploration of these pathways revealed that Epo is also an angiogenic as well as an anti-apoptotic factor as described respectively in the brain [52] and the heart [47,50,53,54]. As previously described [55], chronic hypoxia led to the activation of HIF-1α/VEGF pathway in the heart of adult wild-type mice most probably responsible for their enhanced myocardial angiogenesis.…”

Section: Heart Under Chronic Hypoxiamentioning

confidence: 99%

“…Many other molecules, including Epo, VEGF and iNOS have also been shown to be upregulated in the anemic brain [61,65]. Thus, it seems that during anemia, HIF-1α has the potential to regulate cerebral cellular responses under both hypoxic and normoxic conditions [23,47,57,64,65].…”

Section: Brain Under Chronic Anemiamentioning

confidence: 99%

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Adaptations to Chronic Hypoxia Combined with Erythropoietin Deficiency in Cerebral and Cardiac Tissues

Hasnaoui-Saadani¹

2017

Hypoxia and Human Diseases

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Chronic anemia-induced hypoxia triggers regulatory pathways that mediate long-term adaptive cardiac and cerebral changes, particularly at the transcriptional level. These adaptative mechanisms include a regulated cerebral blood low and cardiac output, angiogenesis and cytoprotection triggered by hypoxia-inducible factor 1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), neuronal nitric oxide synthase (nNOS) and Epo pathways. All these compensatory mechanisms aim to optimize oxygen delivery and to protect the brain and heart from hypoxic injury. We reviewed the efects of chronic hypobaric hypoxia as well as chronic anemia in the heart and brain, and we compared for the irst time the efects of chronic hypobaric hypoxia combined with a severe lack of Epo (chronic anemia) in these vital organs. Functional cardiac adaptations such as cardiac hypertrophy, increased cardiac output as well as angiogenesis occurred along with the activation of HIF1α/VEGF and Epo/EpoR pathways under chronic anemia or hypoxia. Similarly, cerebrovascular adaptations take place through the same molecular mechanisms under chronic hypoxia or anemia. However, when both arterial pressure and content of oxygen are decreased, the cerebral and cardiac adaptative mechanisms showed their limitations. In addition, cerebral and cardiac cell injuries may have occurred following the combined efect of chronic anemia and hypoxia. By emphasizing the anemia and hypoxia-induced cerebral and myocardial adaptations, this review highlighted the crucial role of Epo in its non-erythropoietic functions such as angiogenesis and neuroprotection. Indeed, a beter understanding of these protective mechanisms is of great clinical importance to the development of new therapeutic strategies for the management of ischemic heart and brain.

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Section: Heart Under Chronic Hypoxiamentioning

confidence: 78%

Section: Brain Under Chronic Anemiamentioning

confidence: 89%

Section: Heart Under Chronic Hypoxiamentioning

confidence: 99%

Section: Heart Under Chronic Hypoxiamentioning

confidence: 99%

Section: Brain Under Chronic Anemiamentioning

confidence: 99%

See 3 more Smart Citations

Adaptations to Chronic Hypoxia Combined with Erythropoietin Deficiency in Cerebral and Cardiac Tissues

Hasnaoui-Saadani¹

2017

Hypoxia and Human Diseases

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Erythropoietin enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia through Akt/eNOS signalling pathway

Qin

Zhou

et al. 2014

Cell Biology International

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Adaptation of cardiomyocytes to chronic hypoxia in cyanotic patients remains unclear. Mitochondrial biogenesis is enhanced in myocardium from cyanotic patients, which is possibly an adaptive response. Erythropoietin (EPO) in blood and its receptor (EPOR) on cardiomyocytes are upregulated by chronic hypoxia, suggesting that EPO-EPOR interaction is increased, which is inferred to positively regulate mitochondrial biogenesis through protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signalling pathway. H9c2 cardiomyocytes were exposed to hypoxia (1% O(2)) for 1 week and treated with different doses of recombinant human erythropoietin (rhEPO). Mitochondrial number, mitochondrial DNA (mtDNA) copy number and peroxisome proliferator activated receptor gamma coactivator alpha (PGC-1α) mRNA expression increased in a dose-dependent manner induced by rhEPO. Akt and eNOS were significantly phosphorylated by rhEPO. Both blocking Akt with Wortmannin and silencing eNOS expression with shRNA plasmid decreased the mtDNA copy number and PGC-1α mRNA expression induced by rhEPO. Blocking Akt was associated with the decreased phosphorylation of Akt and eNOS. RNA interference led to a reduction in the total and phosphorylated proteins of eNOS. Thus EPO enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia, at least partly through Akt/eNOS signalling, which might be an adaptive mechanism of cardiomyocytes associated with the increased EPO-EPOR interaction in patients with cyanotic congenital heart disease (CCHD).

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Vascular characteristics and expression of hypoxia genes in Tibetan pigs’ hearts

Yang

Gao

Yang

et al. 2021

Veterinary Medicine & Sci

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Background: Tibetan pigs have exhibited unique characteristics from low-altitudes pigs and adapted well to the Qinghai-Tibet Plateau. Objectives:The current study was undertaken to investigate the hypoxic adaptation of heart in Tibetan pigs. Methods:The hearts of Tibetan pigs and Landrace pigs raised at high or low altitudes were compared using 3D casting technology, scanning electron microscopy and realtime quantitative PCR (qRT-PCR). Results:We found that the ratio of the major axis to the minor axis and the density of the heart were significantly higher in Tibetan pigs than in Landrace pigs (p < 0.05).Tibetan pigs had larger diameters and higher densities of arterioles than Landrace pigs (p < 0.05), and these features have a similar variation with the expression of vascular endothelial growth factor (VEGF). The cardiac expression levels of hypoxia-inducible factor-1α (HIF-1α) and endothelial nitric oxide synthase (eNOS) were significantly higher in pigs reared at high altitudes than in those reared at low altitudes (p < 0.05).In contrast, Egl nine homolog 1 (EGLN1) had the opposite trend with respect to HIF-1α and eNOS and was related to red blood cell (RBC) counts. Notably, the expressions of erythropoietin (EPO) and endothelial PAS domain-containing protein 1 (EPAS1) were significantly higher in Landrace pigs kept at high altitudes than in the others (p < 0.05) and were associated with haemoglobin.Conclusions: These findings show that the regulation of the heart function of Tibetan pigs in a hypoxic environment is manifested at various levels to ensure the circulation of blood under extreme environmental conditions.

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Epo deficiency alters cardiac adaptation to chronic hypoxia

Cited by 19 publications

References 32 publications

Adaptations to Chronic Hypoxia Combined with Erythropoietin Deficiency in Cerebral and Cardiac Tissues

Adaptations to Chronic Hypoxia Combined with Erythropoietin Deficiency in Cerebral and Cardiac Tissues

Erythropoietin enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia through Akt/eNOS signalling pathway

Vascular characteristics and expression of hypoxia genes in Tibetan pigs’ hearts

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