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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.

The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high energy phosphate metabolism Thumbnail


Authors

Mary Slingo

MARK COLE MARK.COLE@NOTTINGHAM.AC.UK
Assistant Professor

Carolyn Carr

Mary K. Curtis

Michael Dodd

Lucia Giles

Lisa C. Heather

Damian Tyler

Kieran Clarke

Peter A. Robbins



Abstract

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.

Journal Article Type Article
Acceptance Date Jul 12, 2016
Online Publication Date Jul 15, 2016
Deposit Date Jul 13, 2016
Publicly Available Date Jul 15, 2016
Journal American Journal of Physiology – Heart and Circulatory Physiology
Print ISSN 0363-6135
Electronic ISSN 1522-1539
Publisher American Physiological Society
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1152/ajpheart.00912.2015
Keywords Hypoxia-inducible factor, cardiac metabolism, MRI, hyperpolarized pyruvate, Chuvash polycythemia
Public URL https://nottingham-repository.worktribe.com/output/800913
Publisher URL http://ajpheart.physiology.org/content/early/2016/07/12/ajpheart.00912.2015

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