Insights from Ectothermic Vertebrates: Programming Cardiac Hypoxia Tolerance

点击翻译按钮获取中文摘要

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".