Interplay between Iron and Oxygen Homeostasis in Systems (Patho)physiology
What we study
We study how iron is regulated at the autocrine and paracrine levels, and how its availability impinges on normal systems physiology, and on responses to (patho)physiological stimuli such as hypoxia.
Why is it important?
By dissecting the iron regulatory pathways that operate in the "healthy" state, we can begin to understand the disease processes associated with iron imbalance and maladaptive responses to hypoxia. Ultimately, such mechanistic understanding should pave the way for the development of preventive and therapeutic iron manipulation strategies for these diseases.
The Heart as a Model System
We are interested in the cardiovascular system because a) it is particularly sensitive to changes in iron balance, and b) it offers a paradigm for the interplay between iron and oxygen homeostasis at the pathophysiological level.
a) The cardiovascular system is particularly sensitive to changes in iron balance: Indeed, cardiomyopathy is the leading cause of morbidity and mortality in conditions of iron overload such haemochromatosis, and in β-thalassaemia with transfusional overload. Furthermore, human studies indicate a strong link between total body iron levels and risk of myocardial infarction and this is further supported by the finding that iron participates in the signalling pathways of atherosclerosis. As well as being implicated in the aetiology of myocardial infarction, it has now been established that cardiac iron also participates in the process of reperfusion injury and that iron chelation prior to interruption of blood flow reduces myocardial infarct size and oxidative injury upon reperfusion in animal models. Interestingly, a seminal trial in 459 patients with chronic heart failure and iron deficiency concluded that correction of iron deficiency improves symptoms, functional capacity, and quality of life both in anaemic and non-anaemic subjects, although the mechanisms underlying these findings remain unknown. Thus, there is a strong body of evidence that, depending on the specific disease context, iron excess or iron deficiency can contribute to or exacerbate heart disease. Exploitation of iron depletion or supplementation for therapeutic purposes warrants molecular understanding of the pathways that control iron levels in the heart.
b) The cardiovascular system as a paradigm for the interplay between iron and oxygen homeostasis at the pathophysiological level: Both systemic and localised hypoxia (ischemia) engender significant responses in the heart. Systemic hypoxia induces an increase in cardiac output, necessitating quantitative and qualitative changes in energy production in the cardiac muscle. Localised hypoxia, exemplified by ischemic heart disease, also impinges on cardiac function by multiple mechanisms, such as the generation of ROS and altered redox equilibrium. The Hypoxia-inducible factors HIFs are master transcription factors that orchestrate cellular and systemic responses to hypoxia. In the cardiovascular system, they are implicated in the response to systemic and localized hypoxia. Intriguingly, the molecular sensors (prolyl hydroxylases PHDs) that regulate HIFs in response to oxygen levels also require iron as a co-factor, conferring dual responsiveness to iron and oxygen on the HIF system. Together, these findings have lead us and others to postulate that the cardiac response to hypoxia may be phenocopied or potentiated by iron deficiency ,and may be inhibited or attenuated by iron supplementation.
- To identify the molecules that regulate cardiac iron levels. To this end, we have generated novel mouse models that enable cardiac-specific deletion of two important iron-homeostatic proteins ; hepcidin and ferroportin. While the roles of these proteins in systemic iron regulation is well characterized, their specific functions in the heart remain to be formally addressed.
- To understand how cardiac iron levels are altered by physiological stimuli, such as hypoxia. Indeed, as well as being regulated by iron, HIFs, either directly or indirectly, in turn regulate the transcription of multiple iron regulatory genes, including the iron uptake protein TfR, hepcidin, and certain isoforms of ferroportin.
- To assess the relevance of iron metabolism in the cardiac response to hypoxia, both upstream and downstream of HIFs, and through HIF-independent pathways (e.g Iron regulatory proteins IRPs).
- To test the modulatory effects of iron supplementation and depletion on cardiac responses to hypoxia.
Other physiological systems of interest
The pathophysiological interplay between oxygen an iron homeostasis has been demonstrated in seminal human studies carried out by Robbins et al, on hypoxia-induced pulmonary arterial hypertension PAH. They showed that PAH could be exacerbated by iron depletion and attenuated by iron supplementation, although the mechanism remains to be addressed. We aim to use animal models to replicate these findings and interrogate the mechanisms, HIF-dependent or otherwise, through which iron modulates PAH.
The placenta also presents an intriguing system for studying the pathophysiological interplay between oxygen an iron homeostasis. Hypoxia in the first trimester of gestation plays an important role in placental and fetal development. Persistent hypoxia in later stages of gestation has been associated with pre-eclampsia. In this context, little is known about how iron regulates HIFs in the placenta, and how iron itself is regulated at the fetomaternal interface. Again, we aim to address these questions using animal models.
Ms Magda Wolna, Research assistant firstname.lastname@example.org
Ms Yujin Chung, Graduate student email@example.com
1. British Heart Foundation- Intermediate Basic Science Research Fellowship
2. Vifor Pharma Research Grant
3. Medical Research Council Research Grant