Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control

Cheng, Xiaotong; Prange-Barczynska, Maria; Fielding, James W.; Zhang, Minghao; Burrell, Alana; Lima, Joanna Darck Carola Correia; Eckardt, Luise; Argles, Isobel L.A.; Pugh, Christopher W.; Buckler, Keith J.; Robbins, Peter A.; Hodson, Emma J.; Bruick, Richard K.; Collinson, Lucy; Rastinejad, Fraydoon; Bishop, Tammie; Ratcliffe, Peter J.

doi:10.1172/jci133194

Cited by 40 publications

(28 citation statements)

References 49 publications

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“…We were not able to measure ventilation as part of the expedition. Whilst there is good reason to believe iron bioavailability might affect pulmonary ventilation via an action on the hypoxia inducible factor pathway within carotid body glomus cells [ 11 ], no human study has detected such a phenomenon [ 8 , 12 ]. Moreover, the expected direction of effect is for iron to diminish alveolar ventilation rather than augment it.…”

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confidence: 99%

Iron bioavailability and cardiopulmonary function during ascent to very high altitude

et al. 2020

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More than one hundred million people reside worldwide at altitudes in excess of 2500 m above sea level. In the millions more who sojourn at high altitude for recreational, occupational or military pursuits, hypobaric hypoxia drives physiological changes affecting the pulmonary circulation, haematocrit and right ventricle (RV) [1]. Coincident with these, maximal left ventricular (LV) stroke volume (SV) falls [2], with a reduction of 20% reported after a 2-week stay at 4300 m [3]. A rise in heart rate (HR) compensates at rest and during submaximal exercise but is insufficient during maximal intensity exercise, constraining maximal cardiac output (CO). Previously, it was considered that a reduction in plasma volume or a direct effect of hypoxia on LV myocardial contractility were probably responsible [4]. More recently it has been suggested that increased RV afterload may be of greater importance [5].

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confidence: 99%

Iron bioavailability and cardiopulmonary function during ascent to very high altitude

et al. 2020

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“…A recent phase I trial of PT2385 in humans with previously treated, advanced CCRCC reported evidence of anti-tumour activity in 14% patients with a favourable safety profile, although the predictable side-effect of anaemia occurred in 45% patients [211]. Of interest, dyspnoea and hypoxaemia are also recognised side-effects and presumably relate to inhibition of HIF-2α signalling in the carotid body [212]. These drugs may also be effective in treating other tumours in which HIF-2α is implicated in tumorigenesis, including RCCs caused by mutations in FH, SDH, and TCEB1 and PGL/PCC [213,214].…”

Section: Therapeutic Targeting Of Tumour Hypoxia and The Hif Systemmentioning

confidence: 99%

Recent advances in the biology of tumour hypoxia with relevance to diagnostic practice and tissue‐based research

Macklin

Yamamoto

Browning

et al. 2020

The Journal of Pathology

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In this review article, we examine the importance of low levels of oxygen (hypoxia) in cancer biology. We provide a brief description of how mammalian cells sense oxygen. The hypoxia-inducible factor (HIF) pathway is currently the best characterised oxygen-sensing system, but recent work has revealed that mammals also use an oxygen-sensing system found in plants to regulate the abundance of some proteins and peptides with an amino-terminal cysteine residue. We discuss how the HIF pathway is affected during the growth of solid tumours, which develop in microenvironments with gradients of oxygen availability. We then introduce the concept of 'pseudohypoxia', a state of constitutive, oxygen-independent HIF system activation that occurs due to oncogenic stimulation in a number of specific tumour types that are of immediate relevance to diagnostic histopathologists. We provide an overview of the different methods of quantifying tumour hypoxia, emphasising the importance of pre-analytic factors in interpreting the results of tissue-based studies. Finally, we review recent approaches to targeting hypoxia/HIF system activation for therapeutic benefit, the application of which may require knowledge of which hypoxia signalling components are being utilised by a given tumour.

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“…It is well recognised that time-dependent augmentation of HVR and thus increased ventilation accompanies adaptation to altitude [113,150]. In this respect, a recent study has highlighted the role of carotid body activation and type I cell proliferative responses to sustained hypoxia during ventilatory acclimatisation, a process that is mediated by HIF-2α, and abrogated by its inhibition [151]. However, evidence suggests that ventilatory acclimatisation is, at least in part, also determined by adjustment of NTS afferent inputs to RVLM [152], where regulation of AMPK-α1 expression [107] and consequent adjustments to AMPK-dependent facilitation of HVR may come in to play [10,112].…”

Section: Regulation Of Oxygen Supply Feeding and Food Choice During mentioning

confidence: 99%

AMPK and the Need to Breathe and Feed: What’s the Matter with Oxygen?

Evans

Hardie

2020

IJMS

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We live and to do so we must breathe and eat, so are we a combination of what we eat and breathe? Here, we will consider this question, and the role in this respect of the AMP-activated protein kinase (AMPK). Emerging evidence suggests that AMPK facilitates central and peripheral reflexes that coordinate breathing and oxygen supply, and contributes to the central regulation of feeding and food choice. We propose, therefore, that oxygen supply to the body is aligned with not only the quantity we eat, but also nutrient-based diet selection, and that the cell-specific expression pattern of AMPK subunit isoforms is critical to appropriate system alignment in this respect. Currently available information on how oxygen supply may be aligned with feeding and food choice, or vice versa, through our motivation to breathe and select particular nutrients is sparse, fragmented and lacks any integrated understanding. By addressing this, we aim to provide the foundations for a clinical perspective that reveals untapped potential, by highlighting how aberrant cell-specific changes in the expression of AMPK subunit isoforms could give rise, in part, to known associations between metabolic disease, such as obesity and type 2 diabetes, sleep-disordered breathing, pulmonary hypertension and acute respiratory distress syndrome.

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Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control

Cited by 40 publications

References 49 publications

Iron bioavailability and cardiopulmonary function during ascent to very high altitude

Iron bioavailability and cardiopulmonary function during ascent to very high altitude

Recent advances in the biology of tumour hypoxia with relevance to diagnostic practice and tissue‐based research

AMPK and the Need to Breathe and Feed: What’s the Matter with Oxygen?

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