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- Cowburn, AS, et al.
(författare)
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HIF isoforms in the skin differentially regulate systemic arterial pressure
- 2013
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 110:43, s. 17570-17575
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Tidskriftsartikel (refereegranskat)abstract
- The differential expression of the hypoxia-inducible factor-alpha (HIF-α) isoforms in the skin of mice influences vascular resistance and is correlated with homeostatic regulation of nitric oxide synthesis. A correlation between HIF isoform expression and hypertension was found in skin biopsies from human subjects, and may indicate a mechanism in the etiology of idiopathic hypertension.
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- Cowburn, AS, et al.
(författare)
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HIF2α-arginase axis is essential for the development of pulmonary hypertension
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 113:31, s. 8801-8806
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Tidskriftsartikel (refereegranskat)abstract
- The expression of hypoxia-inducible factor (HIF)-2α in pulmonary endothelium of mice influences pulmonary vascular resistance and development of hypoxic pulmonary hypertension (PH) via an arginase-1–dependent mechanism. The HIF-2α:arginase-1 axis influences the homeostatic regulation of nitric oxide synthesis in the lung. Impaired generation of this vasoactive agent contributes to the initial development and vascular remodeling process of PH.
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- Macias, D, et al.
(författare)
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HIF-2α is essential for carotid body development and function
- 2018
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Ingår i: eLife. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Mammalian adaptation to oxygen flux occurs at many levels, from shifts in cellular metabolism to physiological adaptations facilitated by the sympathetic nervous system and carotid body (CB). Interactions between differing forms of adaptive response to hypoxia, including transcriptional responses orchestrated by the Hypoxia Inducible transcription Factors (HIFs), are complex and clearly synergistic. We show here that there is an absolute developmental requirement for HIF-2α, one of the HIF isoforms, for growth and survival of oxygen sensitive glomus cells of the carotid body. The loss of these cells renders mice incapable of ventilatory responses to hypoxia, and this has striking effects on processes as diverse as arterial pressure regulation, exercise performance, and glucose homeostasis. We show that the expansion of the glomus cells is correlated with mTORC1 activation, and is functionally inhibited by rapamycin treatment. These findings demonstrate the central role played by HIF-2α in carotid body development, growth and function.
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- Semba, H, et al.
(författare)
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HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 11635-
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Tidskriftsartikel (refereegranskat)abstract
- In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.
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