Insights from Ectothermic Vertebrates: Programming Cardiac Hypoxia Tolerance

The likelihood of a person developing heart disease dramatically increases with age and represents the leading cause of death in people over 65. By 2030, approximately 20% of the population will be aged 65 or older and the cost for treating heart disease will triple. There is an urgent need to develop new treatments for the prevention of heart disease to reduce the welfare and economic burdens of cardiac disease and ensure healthy ageing across the life course. Many cardiac diseases occur as a result of a reduced oxygen supply to the heart. A lack of oxygen, termed hypoxia, triggers fatal cardiac events, such as heart attacks. Ultimately, the chance of a person surviving a heart attack will depend on the sensitivity of their heart to hypoxia. This is particularly relevant in the elderly; not only is there a higher incidence of diseases which cause cardiac hypoxia, but the elderly heart is also less hypoxia-tolerant. The present proposal aims to develop a strategy to permanently enhance an individual's tolerance to cardiac hypoxia, providing life-long protection against heart disease. This aim will be met by taking advantage of a natural biological process called "developmental programming".

Developmental programming is the process by which changes in the prenatal environment can permanently modify a baby's genes, and therefore biology, without changing their basic genetic blueprint. These changes persist into adulthood, and can even be inherited by a person's children and grandchildren. In other words, an individual's biology can be permanently affected by the environment in which their grandmother developed. This astonishing discovery has opened the door for scientists to permanently "programme" aspects of an individual's biology. Indeed, drugs are currently being developed which can artificially modify genes and mimic the effects of developmental programming. These so-called "epidrugs" provide a means to programme cardiac hypoxia tolerance in humans and protect them from heart disease. However, before we can develop these drugs, we need to know which genes need be modified to produce a hypoxia-tolerant heart. In this regard, my laboratory has recently made an exciting and unexpected discovery: altering the developmental environment of a very ancient species of reptile, the snapping turtle, programmes cardiac hypoxia tolerance. This is the only known animal in which this occurs. Although the structure of the turtle heart is different to humans, we share many common genes that regulate heart function. Therefore, the immediate aim of the present proposal is to identify the genes which are modulated to programme cardiac hypoxia tolerance. Our long-term goal is to use this information to develop epidrugs which permanently programme hypoxia tolerance in the human heart, providing life-long protection against heart disease. These goals are strongly aligned to the BBSRC's Strategic Priority of "healthy ageing across the life-course".

The prevalence of heart disease increases dramatically with age and remains the leading cause of death in people over 65. Innovative new strategies are urgently needed to protect the ageing heart from disease. The survival of patients with heart disease ultimately depends on the ability of their cardiomyocytes to tolerate oxygen deprivation (hypoxia). This is particularly relevant in the elderly; not only is there a higher prevalence of diseases which cause cardiac hypoxia but also the elderly heart is less hypoxia-tolerant. Here I present a novel approach for permanently protecting the ageing heart and preventing disease: Developmental programming of cardiomyocyte hypoxia tolerance. The hypoxia sensitivity of the adult heart can be predetermined by events occurring during development. Exposure of mammalian foetuses to chronic hypoxia permanently "programmes" cardiac hypoxia sensitivity. This paradigm is well established; there are no reports of chronic hypoxia programming adaptive cardiac phenotypes. However, I have recently made an unexpected discovery; chronic developmental hypoxia in turtles permanently programmes cardiac hypoxia tolerance with an improvement in cellular efficiency. This fortuitous discovery provides a model system to identify mechanisms which programme cardiac hypoxia tolerance. Identifying these mechanisms have translational relevance; drugs are currently being developed which artificially modify genes and mimic the effects of developmental programming, so-called "epidrugs". Therefore, the immediate aims of the present proposal are: 1) To identify the cellular pathways which are programmed by chronic hypoxia in turtles, and 2) To identify the epigenetic mechanisms underlying the programmed phenotype. The long-term aim is to characterise an epigenetic signature for cardiac hypoxia tolerance which can be utilised to develop epidrugs that permanently protect the human heart from hypoxia, providing life-long protection against disease.

Clinicians: Engaging clinicians with clinically-relevant research is essential for the translation of research outputs into improved patient outcomes. Clinicians are at the front-line of a patient's health needs being addressed and delivered. Therefore, clinicians have a long-term vested interest in understanding basic scientific principles and new paradigms (such as epigenetics) that will shape future novel therapeutic interventions. The immediate aim of our impact plan is to engage clinicians with a novel and translatable model for protecting the human heart against oxygen-related disease. The long-term impact of this partnership will be enhancing the nation's health and quality of life.

Patients: Ultimately, the main beneficiaries of our research are patients. Numerous diseases in humans develop as a result of the exquisite hypoxia sensitivity of mammalian tissues and organs. This is especially true for organs with high energy demands, such as the heart. Identifying genes which are epigenetically programmed to produce a hypoxia-tolerant heart will lead to identification of new drug targets and, eventually, novel therapeutic interventions that will protect the heart against disease. Drug discovery scientists are now in the process of creating drugs which interfere with epigenetic marks. These studies provide a means (in the long term) to translate our research into therapeutic interventions which will improve the nation's health/ quality of life.

Environmental charities and policy makers: Developmental plasticity is a vital factor in determining the likelihood of an organism surviving climate change. It is crucial to raise awareness of this concept within the environmental conservation communities, ranging from third sector charities to government policy makers, such as the Environment Agency. Disseminating the implications of our research to these beneficiaries will inform policy-makers and increase the effectiveness of public services.

The post-doctoral researcher: The researcher will develop academic and professional skills to apply in other employment sectors, such as drug discovery, environmental management and health care.

The wider public: Developmental programming and epigenetics has received considerable press attention recently, mainly due to the implications for health and disease. Much of the information released to the general public has been criticised for putting unnecessary pressure on pregnant women and leading to a culture of "scaremongering". We are committed to disseminating our research to the general public in an accurate and ethical way to promote human health and well-being. Our research will provide a more positive outlook on developmental programming effects, and will inform the general public on the utility of studying organisms that have naturally evolved stress-resistance. International outreach to the American public (via the proposal collaborator) will impact the UK's scientific visibility in the USA. Collectively, disseminating our research to the wider public will enhance the public awareness of science, and the quality of life, health and creative output of the UK.