The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism
Hypoxia-inducible factor (HIF) appears to function as a global master regulator of cellular and systemic responses to hypoxia. HIF-pathway manipulation is of therapeutic interest, however global, systemic upregulation of HIF may have as yet unknown effects on multiple processes. We utilized a mouse...
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American Physiological Society
2016
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| Online Access: | https://eprints.nottingham.ac.uk/34954/ |
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| author | Slingo, Mary Cole, Mark Carr, Carolyn Curtis, Mary K. Dodd, Michael Giles, Lucia Heather, Lisa C. Tyler, Damian Clarke, Kieran Robbins, Peter A. |
| author_facet | Slingo, Mary Cole, Mark Carr, Carolyn Curtis, Mary K. Dodd, Michael Giles, Lucia Heather, Lisa C. Tyler, Damian Clarke, Kieran Robbins, Peter A. |
| author_sort | Slingo, Mary |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Hypoxia-inducible factor (HIF) appears to function as a global master regulator of cellular and systemic responses to hypoxia. HIF-pathway manipulation is of therapeutic interest, however global, systemic upregulation of HIF may have as yet unknown effects on multiple processes. We utilized a mouse model of Chuvash polycythemia (CP), a rare genetic disorder which modestly increases expression of HIF target genes in normoxia, to understand what these effects might be within the heart.
An integrated in and ex vivo approach was employed. In comparison to wild-type controls, CP mice had evidence (using in vivo MRI) of pulmonary hypertension, right ventricular hypertrophy, and increased left ventricular ejection fraction. Glycolytic flux (measured using 3H glucose) in the isolated, contracting, perfused CP heart was 1.8-fold higher. Net lactate efflux was 1.5-fold higher. Furthermore, in vivo 13C magnetic resonance spectroscopy (MRS) of hyperpolarized 13C1 pyruvate revealed a 2-fold increase in real-time flux through lactate dehydrogenase in the CP hearts, and a 1.6-fold increase through pyruvate dehydrogenase. 31P MRS of perfused CP hearts under increased workload (isoproterenol infusion) demonstrated increased depletion of phosphocreatine relative to ATP. Intriguingly, no changes in cardiac gene expression were detected.
In summary, a modest systemic dysregulation of the HIF pathway resulted in clear alterations in cardiac metabolism and energetics. However, in contrast to studies generating high HIF levels within the heart, the CP mice showed neither the predicted changes in gene expression nor any degree of LV impairment. We conclude that the effects of manipulating HIF on the heart are dose-dependent.
New and noteworthy
This is the first integrative metabolic and functional study of the effects of modest HIF manipulation within the heart. Of particular note, the combination (and correlation) of perfused heart metabolic flux measurements with the new technique of real-time in vivo MR spectroscopy using hyperpolarized pyruvate is a novel development. |
| first_indexed | 2025-11-14T19:24:39Z |
| format | Article |
| id | nottingham-34954 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:24:39Z |
| publishDate | 2016 |
| publisher | American Physiological Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-349542020-05-04T18:01:23Z https://eprints.nottingham.ac.uk/34954/ The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism Slingo, Mary Cole, Mark Carr, Carolyn Curtis, Mary K. Dodd, Michael Giles, Lucia Heather, Lisa C. Tyler, Damian Clarke, Kieran Robbins, Peter A. Hypoxia-inducible factor (HIF) appears to function as a global master regulator of cellular and systemic responses to hypoxia. HIF-pathway manipulation is of therapeutic interest, however global, systemic upregulation of HIF may have as yet unknown effects on multiple processes. We utilized a mouse model of Chuvash polycythemia (CP), a rare genetic disorder which modestly increases expression of HIF target genes in normoxia, to understand what these effects might be within the heart. An integrated in and ex vivo approach was employed. In comparison to wild-type controls, CP mice had evidence (using in vivo MRI) of pulmonary hypertension, right ventricular hypertrophy, and increased left ventricular ejection fraction. Glycolytic flux (measured using 3H glucose) in the isolated, contracting, perfused CP heart was 1.8-fold higher. Net lactate efflux was 1.5-fold higher. Furthermore, in vivo 13C magnetic resonance spectroscopy (MRS) of hyperpolarized 13C1 pyruvate revealed a 2-fold increase in real-time flux through lactate dehydrogenase in the CP hearts, and a 1.6-fold increase through pyruvate dehydrogenase. 31P MRS of perfused CP hearts under increased workload (isoproterenol infusion) demonstrated increased depletion of phosphocreatine relative to ATP. Intriguingly, no changes in cardiac gene expression were detected. In summary, a modest systemic dysregulation of the HIF pathway resulted in clear alterations in cardiac metabolism and energetics. However, in contrast to studies generating high HIF levels within the heart, the CP mice showed neither the predicted changes in gene expression nor any degree of LV impairment. We conclude that the effects of manipulating HIF on the heart are dose-dependent. New and noteworthy This is the first integrative metabolic and functional study of the effects of modest HIF manipulation within the heart. Of particular note, the combination (and correlation) of perfused heart metabolic flux measurements with the new technique of real-time in vivo MR spectroscopy using hyperpolarized pyruvate is a novel development. American Physiological Society 2016-07-15 Article PeerReviewed Slingo, Mary, Cole, Mark, Carr, Carolyn, Curtis, Mary K., Dodd, Michael, Giles, Lucia, Heather, Lisa C., Tyler, Damian, Clarke, Kieran and Robbins, Peter A. (2016) The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism. American Journal of Physiology – Heart and Circulatory Physiology . ISSN 1522-1539 Hypoxia-inducible factor cardiac metabolism MRI hyperpolarized pyruvate Chuvash polycythemia http://ajpheart.physiology.org/content/early/2016/07/12/ajpheart.00912.2015 doi:10.1152/ajpheart.00912.2015 doi:10.1152/ajpheart.00912.2015 |
| spellingShingle | Hypoxia-inducible factor cardiac metabolism MRI hyperpolarized pyruvate Chuvash polycythemia Slingo, Mary Cole, Mark Carr, Carolyn Curtis, Mary K. Dodd, Michael Giles, Lucia Heather, Lisa C. Tyler, Damian Clarke, Kieran Robbins, Peter A. The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism |
| title | The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism |
| title_full | The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism |
| title_fullStr | The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism |
| title_full_unstemmed | The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism |
| title_short | The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism |
| title_sort | von hippel-lindau chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism |
| topic | Hypoxia-inducible factor cardiac metabolism MRI hyperpolarized pyruvate Chuvash polycythemia |
| url | https://eprints.nottingham.ac.uk/34954/ https://eprints.nottingham.ac.uk/34954/ https://eprints.nottingham.ac.uk/34954/ |