The role of the hypoxia-inducible pathway in metabolism and cardiopulmonary physiology

Thesis

The research in this thesis investigated the role of the hypoxia-inducible factor (HIF) family of transcription factors in metabolism and cardiopulmonary physiology. Specifically, the effects of HIF on ventilatory control, carotid body morphology, and cardiac metabolism and function were studied using a murine model of a genetic disorder of oxygen sensing known as Chuvash polycythaemia.

HIF coordinates oxygen-regulated gene expression throughout all organ systems, thereby orchestrating cellular, tissue and systemic responses to hypoxia. HIF is primarily regulated by oxygen-dependent prolyl hydroxylase-domain enzymes (PHDs) that initiate its degradation via the von Hippel-Lindau protein (VHL). In Chuvash polycythaemia, a homozygous VHL mutation in humans causes generalised stabilisation of HIF in euoxia, resulting in profound changes in cardiopulmonary physiology, exercise and metabolism. The Chuvash mouse model provides an opportunity to further characterise the role of HIF in different organ systems.

Chapter 2 of this thesis introduces the murine model, demonstrating an increase in haemoglobin and haematocrit in the Chuvash mice as well as a marked reduction in body weight.

Chapter 3 describes the ventilatory and carotid body study. Chuvash mice were shown to have elevated baseline ventilation in euoxia and marked ventilatory sensitivity to hypoxia. These findings were accompanied by changes within the carotid body, including hyperplasia, hypertrophy and altered ultrastructure of the oxygen-sensing type I cells.

Chapter 4 of this thesis describes the study into cardiac metabolism, energetics and function. Chuvash hearts were found to have increased glycolytic flux and lactate production (the latter both in and ex vivo), with altered myocardial energetics. Despite this, left ventricular function remained normal, although in vivo cine MRI revealed clear evidence of pulmonary hypertension and right ventricular hypertrophy.

Overall, this thesis provides evidence that the PHD-VHL-HIF axis plays a major role in calibrating the hypoxic response in the principal organ systems responsible for oxygen uptake, delivery and utilisation.

Authors: Slingo, ME

• Publication date: 2013
• DOI: 10.5287/ora-gpzorxvbe
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Chuvash polycythaemia; heart; hypoxia; HIF; carotid-body; ventilation; metabolism
• Subjects: Physiology; Metabolism; Cardiovascular disease