Ventilatory and hematopoietic responses to chronic hypoxia in two rat strains

Ou, L.C.; Chen, J.; Fiore, Emilio; Leiter, James C.; Brinck‐Johnsen, Truls; Birchard, Geoffrey F.; Clemons, Gisela K.; Smith, Robert P.

doi:10.1152/jappl.1992.72.6.2354

Cited by 28 publications

(42 citation statements)

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“…To test whether hypoxia causes skeletal muscle atrophy regardless of nutritional status, 10 rats were exposed to 6,300 m for 21 days (H group) and compared with (31), supporting the existence of marked hypoxemia. Consistently, the adaptation to hypoxic stress was illustrated by the increase in hematocrit in H vs. C and PF animals ( Table 2).…”

Section: Resultsmentioning

confidence: 99%

Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia

Favier

Costes

Defour

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

104

114

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Although it is well established that chronic hypoxia leads to an inexorable loss of skeletal muscle mass in healthy subjects, the underlying molecular mechanisms involved in this process are currently unknown. Skeletal muscle atrophy is also an important systemic consequence of chronic obstructive pulmonary disease (COPD), but the role of hypoxemia in this regulation is still debated. Our general aim was to determine the molecular mechanisms involved in the regulation of skeletal muscle mass after exposure to chronic hypoxia and to test the biological relevance of our findings into the clinical context of COPD. Expression of positive and negative regulators of skeletal muscle mass were explored 1) in the soleus muscle of rats exposed to severe hypoxia (6,300 m) for 3 wk and 2) in vastus lateralis muscle of nonhypoxemic and hypoxemic COPD patients. In rodents, we observed a marked inhibition of the mammalian target of rapamycin (mTOR) pathway together with a strong increase in regulated in development and DNA damage response 1 (REDD1) expression and in its association with 14-3-3, a mechanism known to downregulate the mTOR pathway. Importantly, REDD1 overexpression in vivo was sufficient to cause skeletal muscle fiber atrophy in normoxia. Finally, the comparative analysis of skeletal muscle in hypoxemic vs. nonhypoxemic COPD patients confirms that hypoxia causes an inhibition of the mTOR signaling pathway. We thus identify REDD1 as a negative regulator of skeletal muscle mass during chronic hypoxia. Translation of this fundamental knowledge into the clinical investigation of COPD shows the interest to develop therapeutic strategies aimed at inhibiting REDD1.

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Section: Resultsmentioning

confidence: 99%

Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia

Favier

Costes

Defour

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

104

114

View full text Add to dashboard Cite

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“…In contrast to their acute hypoxic resistance, Hilltop rats are sensitive to chronic hypoxic exposure, developing exaggerated polycythemia, pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy, resembling chronic mountain sickness (CMS) in humans. Divergent responses to hypoxia between the strains do not appear to be related to ventilatory, endocrine, fluid handling capabilities, or initial blood gas differences (Ou et al, 1992;Ou et al, 1994;Colice et al, 1995). Several studies suggest that blunted pulmonary vasoconstriction during acute hypoxia in Hilltop rats may be mediated by differences in nitric oxide-mediated vascular relaxation (Salameh et al, 1999;Karamsetty et al, 2001).…”

Section: Introductionmentioning

confidence: 96%

“…Compared to Madison strain Sprague-Dawley rats, the Hilltop strain is resistant to acute hypoxic pulmonary vasoconstriction and pulmonary leak, resembling high altitude pulmonary edema (HAPE) in humans West et al, 1995). Comparisons of the physiological responses to hypoxia between the Hilltop and Madison strains have been extensively described since the early 1980s (Ou et al, 1984;Langleben et al, 1987;Ou et al, 1992;Colice et al, 1995;Salameh et al, 1999). In contrast to their acute hypoxic resistance, Hilltop rats are sensitive to chronic hypoxic exposure, developing exaggerated polycythemia, pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy, resembling chronic mountain sickness (CMS) in humans.…”

Section: Introductionmentioning

confidence: 99%

Acute Hypobaric Hypoxia (5486 m) Induces Greater Pulmonary HIF-1 Activation in Hilltop Compared to Madison Rats

Engebretsen

Irwin

Valdez

et al. 2007

High Altitude Medicine & Biology

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Compared to Madison strain Sprague-Dawley rats, the Hilltop strain is resistant to acute hypoxic pulmonary vasoconstriction and pulmonary leak, a pathology resembling high altitude pulmonary edema (HAPE) in humans. Hypoxia inducible transcription factor-1 (HIF-1) mediates transcription of proteins that can "rescue" tissue from hypoxia, including vasoactive and angiogenic proteins such as inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF). Because these proteins have theoretical relevance to the etiology of HAPE, we hypothesized that hypoxia-resistant Hilltop rats acutely exposed to high altitude would have greater HIF-1 activity and expression of iNOS and VEGF as compared to hypoxia-sensitive Madison rats. Animals were exposed to normobaric normoxia or hypobaric hypoxia (18 h at 5486 m). The presence of nuclear HIF-1 heterodimer subunits, HIF-1-DNA binding, and iNOS and VEGF protein expression were determined in lung tissue. Hypoxic HIF-1beta expression, HIF-1-DNA binding, and iNOS and VEGF expression were greater in Hilltop than in Madison rats. After 18-h hypobaric hypoxia, HIF-1 activity and HIF-mediated protein expression were elevated in Hilltop rats, but not in Madison rats. To our knowledge, this is the first report of differing HIF-1 activation between two strains of animals with clearly divergent physiological responses to identical hypoxic conditions.

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“…It has been reported in various publications that whereas evident splenomegaly arises in primary polycythemia, there is no apparent change in splenic volume in secondary polycythemia. [1][2][3][4][5] In addition, it has been reported in some organometric studies that hyperplastic changes occur in organs such as the heart and lung that function more to meet the body's oxygen requirements. 6,7 A loss of volume in various organs has been observed in rat studies in which a high-altitude environment was established using pressure chambers.…”

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confidence: 99%