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06.12.2023 | Research Article

Multimodal Imaging Reveals that Sustained Inhibition of HIF-Prolyl Hydroxylases Induces Opposing Effects on Right and Left Ventricular Function in Healthy Rats

verfasst von: Gain Robinson, Mark Zielstorff, Raquel Sevilla, Amy Vanko, Christopher Sinz, Milenko Cicmil, Weisheng Zhang, Kimberly Bettano

Erschienen in: Molecular Imaging and Biology | Ausgabe 1/2024

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Abstract

Purpose

Hypoxia-inducible factor (HIF) drives transcription of critical hypoxia response genes, increasing the production of red blood cells in low oxygen conditions. In the absence of hypoxia, HIF is degraded by prolyl hydroxylases (HIF-PHs). Pharmacological HIF-PH inhibition stabilizes HIF and is being studied as a treatment for anemia. However, like sustained hypoxia, HIF-PH inhibition may increase pulmonary arterial pressure leading to right ventricular hypertrophy. The aim of this study was to assess the cardiac effects of sustained pharmacological HIF-PH inhibition using multimodal imaging, blood analysis, and histology.

Methods

Rats were dosed daily with a pan HIF-PH inhibitor or vehicle for 4 weeks followed by a 2-week washout period and underwent longitudinal magnetic resonance imaging (MRI) and echocardiography to simultaneously assess RV and LV function. Blood samples from weeks four and six were analyzed to determine red blood cell composition. Histology was performed on the cardiac tissue from a subset of rats at weeks four and six to assess structural effects.

Results

Imaging revealed that RV ejection fraction was reduced in animals receiving HIF-PH inhibitor and resulted in RV hypertrophy. Interestingly, HIF-PH inhibition had the opposite effect on the left ventricle (LV), increasing contractility measured by LV ejection fraction. LV effects were reversed by week six, while RV effects (functional and structural) were sustained.

Conclusion

These opposing cardiac effects of HIF-PH inhibition warrant further study to both understand the potential negative effects on RV structure and function and investigate the therapeutic potential of increased LV contractility for conditions like heart failure.

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Titel: Multimodal Imaging Reveals that Sustained Inhibition of HIF-Prolyl Hydroxylases Induces Opposing Effects on Right and Left Ventricular Function in Healthy Rats
verfasst von: Gain Robinson
Mark Zielstorff
Raquel Sevilla
Amy Vanko
Christopher Sinz
Milenko Cicmil
Weisheng Zhang
Kimberly Bettano
Publikationsdatum: 06.12.2023
Verlag: Springer International Publishing
Erschienen in: Molecular Imaging and Biology / Ausgabe 1/2024
Print ISSN: 1536-1632
Elektronische ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-023-01876-9

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Multimodal Imaging Reveals that Sustained Inhibition of HIF-Prolyl Hydroxylases Induces Opposing Effects on Right and Left Ventricular Function in Healthy Rats