Chronic hypoxia: A model for cyanotic congenital heart defects

Corno, Antonio F.; Milano, Giuseppina; Samaja, Michele; Tozzi, Piergiorgio; Segesser, Ludwig K. von

doi:10.1067/mtc.2002.121302

Cited by 71 publications

(57 citation statements)

References 29 publications

(55 reference statements)

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“…This issue is important because the half-life of HIF-1␣ in reoxygenated cell cultures is as short as few minutes (22,23). In addition, certain phenotypes produced by CH are profoundly affected by even short reoxygenation episodes (19,(24)(25)(26). The selected experimental protocol thus represents a model for CH that may arise either from physiological situations as high altitude and airline flights or pathological conditions as congenital heart disease, anemia, carbon monoxide poisoning, or chronic lung diseases.…”

Section: Discussionmentioning

confidence: 99%

Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia

Fantacci

Bianciardi

Caretti

et al. 2006

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

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Ischemia and chronic hypoxia (CH) trigger a variety of adverse effects arising from metabolic stress that injures cells. In response to reduced O 2, hypoxia-inducible factor 1␣ (HIF-1␣) activates erythropoietin (Epo) as well as many other target genes that counteract the effects of O 2 deficiency. Epo produced by the kidney stimulates erythrocyte production, leading to decreased HIF-1␣ production by improved tissue O 2 delivery. However, Epo is produced by many other tissues, and it is currently unclear to what extent, if any, locally produced Epo modulates HIF-1␣ expression. Derivatives of Epo that possess tissue-protective activities but do not stimulate erythropoiesis [e.g., carbamylated Epo (CEpo)] are useful tools with which to determine whether exogenous Epo modulates HIF-1␣ in the absence of changes in hemoglobin concentration. We compared the effects of CH (6.5% O 2 for 10 days) with or without CEpo administered by daily s.c. injection (10 g͞kg of body weight). CEpo administration did not alter the survival rate, weight loss, or increased hemoglobin concentration associated with CH. Therefore, CEpo does not directly suppress HIF-mediated erythropoiesis. CEpo does, however, prevent CH-induced neuronal increases of HIF-1␣ and Epo receptor-associated immunoreactivity (a measure of stress) while reducing the apoptotic index. In contrast, the myocardium did not exhibit increased HIF-1␣ expression during CH, although CEpo did reduce the apoptotic index. These observations therefore demonstrate that CEpo administration reduces the metabolic stress caused by severe CH, resulting in improved cellular survival independent of erythrocyte production.apoptosis ͉ brain ͉ hypoxia-inducible factor 1␣ ͉ heart ͉ Epo receptor

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Section: Discussionmentioning

confidence: 99%

Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia

Fantacci

Bianciardi

Caretti

et al. 2006

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

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“…With many CHDs being characterized by a chronic hypoxic status, the subset of cyanotic children is obviously at a higher risk than the acyanotic CHDs population [59]. Clinical studies have shown that, despite similar cross-clamp times during open heart surgery, cyanotic children have worse clinical outcome and more reoxygenation injury, measured by troponin I release, compared with acyanotic children [11].…”

Section: Reoxygenation and Reperfusion Injuriesmentioning

confidence: 99%

“…As the chronic hypoxia produces long-term changes in the myocardial metabolism and function, the sudden oxygen reintroduction further exacerbates these effects. The impaired contractility due to hypoxia-induced calcium overload and the loss of high energy phosphates are examples of the pathological events amplified by the reoxygenation [59,60]. In addition, the depletion of endogenous antioxidants that characterize chronic cyanosis cannot counteract the oxygen radical-mediated injury when oxygen is reintroduced [61].…”

Section: Reoxygenation and Reperfusion Injuriesmentioning

confidence: 99%

Hypoxia-Induced Molecular and Cellular Changes in the Congenitally Diseased Heart: Mechanisms and Strategies of Intervention

Iacobazzi¹,

Caputo²,

Ghorbel³

2017

Hypoxia and Human Diseases

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Tissue hypoxia plays a critical role in the pathobiology of congenital heart diseases, especially with regard to cyanotic patients. Here, we describe the cellular and molecular mechanisms induced by hypoxia in the diseased heart, with particular attention to the metabolic and functional changes that underlie the hypoxia-induced right ventricle remodelling. The role of reactive oxygen species in transcriptomic changes, DNA damage, contractile dysfunction and extracellular matrix remodelling will be addressed. Furthermore, the reoxygenation injury, which occurs when oxygen is reintroduced upon initiation of cardiopulmonary bypass, will be discussed. This allows a better understanding of the risks associated with the reoxygenation injury in children undergoing openheart surgery and helps to improve strategies of intervention for myocardial protection.

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“…Another potent stimulator of angiogenesis, EC apoptosis and cell arrest is hypoxia. Quite commonly found in various CHDs (110,111), hypoxia may also have an influence on the angiogenic processes in affected children. Indeed, hypoxia has been shown to regulate the expression of different miRs, which have been identified in several cancer cell lines or ECs (112)(113)(114).…”

Section: Regulation Of Angiogenesismentioning

confidence: 99%

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

et al. 2017

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Congenital heart disease (CHD) is the leading cause of infant death, affecting approximately 4-14 live births per 1,000. Although surgical techniques and interventions have improved significantly, a large number of infants still face poor clinical outcomes. MicroRNAs (miRs) are known to coordinately regulate cardiac development and stimulate pathological processes in the heart, including fibrosis or hypertrophy and impair angiogenesis. Dysregulation of these regulators could therefore contribute (I) to the initial development of CHD and (II) at least partially to the observed clinical outcomes of many CHD patients by stimulating the aforementioned pathways. Thus, miRs may exhibit great potential as therapeutic targets in regenerative medicine. In this review we provide an overview of miR function and elucidate their role in selected CHDs, including hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TOF), ventricular septal defects (VSDs) and Holt-Oram syndrome (HOS). We then bridge this knowledge to the potential usefulness of miRs and/or their targets in therapeutic strategies for regenerative purposes in CHDs.

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Chronic hypoxia: A model for cyanotic congenital heart defects

Abstract: Body and blood values are severely affected by chronic hypoxia, and the cardiac effects of uncontrolled reoxygenation after chronic hypoxia are more severe than after acute hypoxia.

Cited by 71 publications

References 29 publications

Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia

Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia

Hypoxia-Induced Molecular and Cellular Changes in the Congenitally Diseased Heart: Mechanisms and Strategies of Intervention

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

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