Cerebral adaptations to chronic anemia in a model of erythropoietin-deficient mice exposed to hypoxia

Hasnaoui-Saadani, Raja El; Pichon, Aurélien; Marchant, Dominique; Olivier, Paul; Launay, Thierry; Quidu, Patricia; Beaudry, Michèle; Duvallet, Alain; Richalet, Jean‐Paul; Favret, Fabrice

doi:10.1152/ajpregu.00119.2008

Cited by 39 publications

(44 citation statements)

References 61 publications

(88 reference statements)

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“…The physiologic role of nNOS and regulation of pVHL/HIF in chronic anemia needs to be addressed (41). In the setting of chronic anemia, changes in SNO bioavailability and S-nitrosothiol signaling may affect angiogenesis as demonstrated in a model of myocardial ischemia (30).…”

Section: Discussionmentioning

confidence: 99%

Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia

Tsui

Marsden²,

Mazer³

et al. 2011

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

103

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Cells sense and respond to changes in oxygen concentration through gene regulatory processes that are fundamental to survival. Surprisingly, little is known about how anemia affects hypoxia signaling. Because nitric oxide synthases (NOSs) figure prominently in the cellular responses to acute hypoxia, we defined the effects of NOS deficiency in acute anemia. In contrast to endothelial NOS or inducible NOS deficiency, neuronal NOS (nNOS) −/− mice demonstrated increased mortality during anemia. Unlike wild-type (WT) animals, anemia did not increase cardiac output (CO) or reduce systemic vascular resistance (SVR) in nNOS −/− mice. At the cellular level, anemia increased expression of HIF-1α protein and HIF-responsive mRNA levels (EPO, VEGF, GLUT1, PDK1) in the brain of WT, but not nNOS −/− mice, despite comparable reductions in tissue PO 2 . Paradoxically, nNOS −/− mice survived longer during hypoxia, retained the ability to regulate CO and SVR, and increased brain HIF-α protein levels and HIF-responsive mRNA transcripts. Real-time imaging of transgenic animals expressing a reporter HIF-α(ODD)-luciferase chimeric protein confirmed that nNOS was essential for anemia-mediated increases in HIF-α protein stability in vivo. S -nitrosylation effects the functional interaction between HIF and pVHL. We found that anemia led to nNOS-dependent S -nitrosylation of pVHL in vivo and, of interest, led to decreased expression of GSNO reductase. These findings identify nNOS effects on the HIF/pVHL signaling pathway as critically important in the physiological responses to anemia in vivo and provide essential mechanistic insight into the differences between anemia and hypoxia.

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Section: Discussionmentioning

confidence: 99%

Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia

Tsui

Marsden²,

Mazer³

et al. 2011

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

103

View full text Add to dashboard Cite

show abstract

“…In the absence of these responses, healthy young mice experience a shift in their mean lethal Hb concentration from 25 gÁL -1 to a higher value near 35 gÁL -1 . 21 Experimental models have shown that these hypoxic cellular responses are also upregulated during chronic anemia 27 and in older hypertensive rodents, 28 suggesting that they may have relevance to both the pediatric and the older adult patient populations that undergo anesthesia for surgical treatment. The overall conclusion from current experimental models strongly suggests that impaired oxygen delivery and tissue hypoxia contribute to increased mortality during acute anemia.…”

Section: Why Is Anemia Unsafe?mentioning

confidence: 99%

Review article: Risks of anemia and related management strategies: can perioperative blood management improve patient safety?

Hare

Freedman

Mazer

2013

Can J Anesth/J Can Anesth

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“…[33][34][35] Our previous studies have demonstrated evidence of increased vascular endothelial growth factor (VEGF) RNA and protein in brain homogenates from anemic rats, suggesting that angiogenesis may be acutely activated. The current microarray data demonstrated that angiopoietin 2 (angiogenic factor) increased progressively after 6 and 24 hr of anemia.…”

Section: Genes Involved In Angiogenesismentioning

confidence: 99%

L’expression génique dans le cortex cérébral de rats anémiques aigus: une analyse par microarray

Briet

Mazer

Tsui

et al. 2009

Can J Anesth/J Can Anesth

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Purpose Hemodilution in perioperative patients has been associated with neurological morbidity and increased mortality by undefined mechanisms. This study assesses whether hemodilutional anemia up-regulated inflammatory cerebral gene expression (microarray) to help define the mechanism. Methods Hemodilution was performed in anesthetized rats by exchanging 50% of the estimated blood volume (30 mL kg -1 ) with pentastarch. Two groups of control animals were utilized, i.e., a non-anesthetized control (Normal Control) and an anesthetized control group (Anesthesia Control). Blood pressure, hemoglobin concentration, and arterial blood gas analysis were performed before and after hemodilution. Cerebral cortex was harvested from isoflurane-anesthetized rats (n = 6) after 6 and 24 hr of recovery and was used to perform complimentary DNA (cDNA) microarray analyses. Pro-inflammatory chemokine and cytokine protein levels were also measured.Results Microarray analysis demonstrated up-regulation of 72 and 27 genes (6 and 24 hr, respectively) in anemic cerebral cortex. These genes were involved in a number of biological functions, including (1) inflammatory responses; (2) angiogenesis; (3) vascular homeostasis; (4) cellular biology; and (5) apoptosis. Chemokine ribonucleic acid (RNA) expression (CXCL-1, -10, and -11) was highest in anemic brain tissue (P \ 0.0125 for each). Protein measurements demonstrated a significant increase in interleukin-6, tumor necrosis factor a, and monocyte chemoattractant protein-1 (P \ 0.05 for each). Conclusion This study utilizes microarray technology to elucidate changes in cerebral cortical gene expression in response to acute hemodilution. These findings demonstrate an increase in pro-inflammatory chemokines (RNA, protein) and cytokines (protein). An improved understanding of the inflammatory response to anemia may help to minimize associated morbidity and mortality. RésuméObjectif L'he´modilution en pe´riope´ratoire chez les patients a e´te´associe´e à une morbidite´neurologique et une mortalite´accrue en raison de me´canismes inde´termine´s. Cette e´tude examine si l'ane´mie par he´modilution re´gule al a hausse l'expression ge´nique ce´re´brale inflammatoire (microarray) afin d'aider a`de´finir ce me´canisme. Méthode Une he´modilution a e´te´re´alise´e chez des rats anesthe´sie´s en e´changeant 50 % du volume sanguin estime( 30 mLÁkg -1 ) avec du pentastarch. Deux groupes d'animaux te´moins ont e´te´utilise´s, soit un groupe te´moin non anesthe´sie´(te´moin normal) et un groupe te´moin anesthe´sie( te´moin anesthe´sie´). La pression arte´rielle, la concentration d'he´moglobine et une gazome´trie sanguine arte´rielle

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Cerebral adaptations to chronic anemia in a model of erythropoietin-deficient mice exposed to hypoxia

Cited by 39 publications

References 61 publications

Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia

Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia

Review article: Risks of anemia and related management strategies: can perioperative blood management improve patient safety?

L’expression génique dans le cortex cérébral de rats anémiques aigus: une analyse par microarray

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