Chronic in vivo hypoxia in various organs: Hypoxia-inducible factor-1α and apoptosis

Bianciardi, Paola; Fantacci, Monica; Caretti, Anna; Ronchi, Raffaella; Milano, Giuseppina; Morel, Sandrine; Segesser, Ludwig von; Corno, Antonio F.; Samaja, Michele

doi:10.1016/j.bbrc.2006.02.042

Cited by 41 publications

(43 citation statements)

References 28 publications

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“…50,51 We first tested this premise indirectly by quantifying the expression of adipose genes known to be upregulated by hypoxic conditions, namely HIF-1a, HIF-2a and GLUT-1. [52][53][54][55] Consistent with our hypothesis, we noted their expression to be increased by quantitative real-time PCR in the adipose tissue of both DIO and ob/ob mice as compared to lean controls. As HIF-1b levels are constitutively expressed and not influenced by hypoxia, one would expect to find equivalent levels in both obese and lean mice, as were our findings here.…”

Section: Discussionsupporting

confidence: 81%

Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration

et al. 2007

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Background: Obesity is currently viewed as a state of chronic low-grade inflammation in which there is a pro-inflammatory alteration in the serum adipocytokine profile as well as an infiltration of white adipose tissue by activated macrophages. The etiology of this inflammation, however, is poorly understood. Methods: Hypothesizing that local hypoxia within expanding white adipose tissue depots may contribute to obesity-related inflammation, we compared body composition, serum inflammatory marker concentrations and the expression of several hypoxia-regulated genes in white adipose tissue derived from lean, dietary-induced obese (DIO) and ob/ob male C57BL/6J mice. We also examined white adipose tissue for the presence of hypoxia using both a pimonidazole-based antibody system and a fiberoptic sensor for real-time pO 2 quantification in vivo. Finally, using cell-specific leukocyte antibodies, we performed immunohistochemistry and flow cytometric analyses to further characterize the cellular nature of adipose inflammation. Results: We determined that obesity in male C57BL/6J mice is associated with increased expression of HIF (hypoxia-inducible factor) isoforms and GLUT-1, and that white adipose tissue hypoxia was present in the obese mice. Immunohistochemistry revealed hypoxic areas to colocalize predominantly with F4/80 þ macrophages. Interestingly, CD3 þ T cells were present in large numbers within the adipose of both DIO and ob/ob obese mice, and flow cytometry revealed their adipose to possess significantly more CD8 þ T cells than their lean cohort. Conclusions: White adipose hypoxia and cytotoxic T-cell invasion are features of obesity in C57BL/6J mice and are potential contributors to their local and generalized inflammatory state.

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Section: Discussionsupporting

confidence: 81%

Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration

et al. 2007

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“…In CH tissues in vivo, HIF-1␣ up-regulation can be sustained. However, this feature is not shared by all organs: whereas brain, muscle, and kidney cortex exhibit sustained HIF-1␣ response, HIF-1␣ is barely detectable in CH myocardium and liver (20), a pattern confirmed in this work. In the heart, it is likely that hypoxia-induced vasodilatation, e.g., produced by local metabolites (29), leads to increases in coronary flow, thereby maintaining adequate O 2 delivery without a need to recruit hypoxia-related mechanisms.…”

Section: Discussionsupporting

confidence: 74%

“…In a model in which rats are exposed to normobaric CH for 15 days, we observed marked deterioration of myocardial protection (19) and sustained apoptosis in a number of organs (20). Although plasma Epo was not measured, an increase in blood Hb by Ͼ70% indicates a substantial Epo stimulation.…”

mentioning

confidence: 95%

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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“…VEGF and VEGF-R2 are known downstream effectors of the hypoxia-inducible factor (HIF)-1α, the master regulator of O 2 homeostasis. Although it is likely that the over-expression of pro-angiogenesis factors depend on the myocardium response to hypoxia, we were unable to document significant changes in HIF-1α protein expression, perhaps due to the short hypoxia times followed by reoxygenation, which blunts HIF-1α protein over-expression [33]. We can't exclude, however, the occurrence of fast peaks in HIF-1α protein levels in the correspondence of the hypoxia bouts.…”

Section: Ih and Angiogenesiscontrasting

confidence: 42%

Impact of phosphatidylinositide 3-kinase signaling pathway on the cardioprotection induced by intermittent hypoxia

et al. 2014

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Chronic in vivo hypoxia in various organs: Hypoxia-inducible factor-1α and apoptosis

Cited by 41 publications

References 28 publications

Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration

Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration

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

Impact of phosphatidylinositide 3-kinase signaling pathway on the cardioprotection induced by intermittent hypoxia

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