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 used a mouse model of Chuvash polycythemia (CP), a rare genetic disorder that 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. Compared with wild-type controls, CP mice had evidence (using in vivo magnetic resonance imaging) of pulmonary hypertension, right ventricular hypertrophy, and increased left ventricular ejection fraction. Glycolytic flux (measured using [(3)H]glucose) in the isolated contracting perfused CP heart was 1.8-fold higher. Net lactate efflux was 1.5-fold higher. Furthermore, in vivo (13)C-magnetic resonance spectroscopy (MRS) of hyperpolarized [(13)C1]pyruvate revealed a twofold increase in real-time flux through lactate dehydrogenase in the CP hearts and a 1.6-fold increase through pyruvate dehydrogenase. (31)P-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.
Highlights
This is the first integrative metabolic and functional study of the effects of modest hypoxia-inducible factor manipulation within the heart
These alterations in substrate utilization may affect myocardial energetics and function: lower phosphocreatine (PCr)-to-ATP ratios were observed in Sherpa hearts [20], in lowlanders exposed to 20 h of normobaric hypoxia [22], and in trekkers travelling to Everest base camp at 5,300 meters [23]
Polycythemia in the Chuvash polycythemia (CP) mice was confirmed by demonstrating a modest increase in both hemoglobin and hematocrit, consistent with previous reports [18, 19, 64]
Summary
This is the first integrative metabolic and functional study of the effects of modest hypoxia-inducible factor manipulation within the heart. It has been hypothesized that myocardial hypoxia, with consequent activation of the HIF pathway, may play a role in altering cardiac substrate utilization, energetics, and contractile function; these changes may cause or exacerbate heart failure. This hypothesis has been explored in experiments producing very high levels of HIF in the heart, from which it is clear that major alterations in HIF give rise to metabolic changes and cardiomyopathy [7, 24, 29, 35, 40, 41]. These experiments do not reveal whether more modest alterations in HIF, at a systemic level, produce similar results
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