Babraham researchers reveal how heart muscle cells get remodelled in response to disease and ageing
11 December 2012
Researchers at the Babraham Institute have discovered how signalling processes within the heart, controlled by a minute molecule known as miR133a, can trigger the development of enlarged heart cells, a process called hypertrophy. Hypertrophy often leads to cardiac failure, which accounts for 25% deaths in the UK and is a primary cause of death in the elderly. Understanding how these pathological changes occur in the heart, in response to disease and ageing, may reveal therapeutic targets and new approaches to treat heart disease, which costs the economy about £9Bn annually.
The study, reported in the Journal of Cell Biology, provides new insight into the mechanisms controlling cardiac growth and the processes driving the adaptation and remodelling of heart muscle. The team has discovered that a microRNA molecule, miR133a, governs the levels of specific receptors (IP3-receptors) produced in heart cells and that interplay between them promotes hypertrophic remodelling of heart muscle. These receptors are channels controlling the movement of calcium ions, which are an important 'messenger' inside cells, regulating heart rhythm and function. If calcium signals occur at the wrong place or time, owing to changes in receptor regulation for example, this can change the heart structure - decreasing its ability to pump efficiently, or trigger irregular heartbeats - arrhythmia.
Immunofluorescence image of ventricular myocyte: Green – ryanodine receptor, red – IP3 receptor, blue – nucleus.
Image: Dr Llewelyn Roderick Group
Dr Faye Drawnel, lead author of the paper said, "Our work has revealed a mechanism for regulating the amount of IP3-receptors made by a heart muscle cell. This is exciting as IP3-receptors are known to promote cardiac growth and arrhythmias that may lead to pathology. They are also found in increased number during human cardiovascular disease conditions. By gaining a better understanding of dysfunctional processes in diseased heart muscle cells, we may discover new therapeutic targets."
Our cardiovascular system adapts, as we age, to cater for the changing needs of the body. If there is a long-term demand to pump more blood - for example during exercise or in pregnancy - the body responds by making the heart cells, known as cardiomyocytes, larger. Conditions like high blood pressure also cause heart growth - 'cardiac hypertrophy' - but in this case increased size does not improve pumping capacity; it promotes the transition to cell death and heart failure as the heart becomes prone to arrhythmias.
Calcium ions are the link between electrical excitation of a myocyte and its contraction. When an electrical impulse arrives at a myocyte, it causes calcium to enter the cell from the outside and also the release of calcium from internal stores, normally a tightly coordinated process. The inositol triphosphate receptor II (IP3RII) calcium channel controls this movement of calcium ions. In hypertrophic heart muscle cells, IP3-receptors release calcium ions, provoking arrhythmias and activating the genes that stimulate cardiac growth. How IP3RII levels are regulated, however, has until recently remained elusive.
Dr LLewelyn Roderick leads the team investigating how calcium levels influence cardiovascular cell function and genes controlling heart size at the Babraham Institute. He explained, "During human heart disease the number of IP3-receptors increases. We discovered that a small RNA, miR133a, controls the level of IP3-receptors produced in cardiomyocytes and that the levels of miR133a, decrease during hypertrophy, to allow cardiac remodelling and make the heart larger. We have shown that preventing miR-133a interacting with IP3RII mRNA increased production of the IP3 receptor, causing hypertrophy in cardiomyocytes."
The paper also reveals that the amount of miR133a itself is determined by calcium released from the IP3-receptors, which themselves initiate a positive feedback loop driving their expression and promoting hypertrophy. Blocking IP3-induced calcium release prevented the repression of miR-133a in response to hypertrophic stimuli, thereby inhibiting the up-regulation of the IP3-receptors. Dr Drawnel explained, "IP3-receptors and miR133a are part of an unstable spiralling loop, whereby an increase in IP3-receptor expression promotes further amplification of the number of IP3-receptors via miR133a. Our next step is to work out how calcium signalling represses miR-133a. Initial findings suggest that the release of calcium switches on an inhibitor of miR-133a expression, which may be an interesting avenue to pursue for therapeutic targets."
MicroRNAs are copied from DNA but do not contain code for protein. Rather, they control gene activity by binding to specific related sequences, thereby interfering with a gene's ability to produce the proteins that co-ordinate cellular activities. Unlike small interfering RNAs that exhibit complete complementarity with their targets, miRNA binding sites (seed sequences) are poorly complementary. A consequence of this is that miRNAs associate with up to several hundred mRNA targets thereby being powerful modifiers of cell phenotype.
The Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC), is a world-leading centre for studying the basic biology of signalling processes inside and between cells, supporting BBSRC's mission to drive advances in fundamental bioscience for better health and improved quality of life. Professor Michael Wakelam, Babraham's Director said, "This fundamental research provides new insight into the mechanisms controlling cardiac growth, adaptation, regeneration and repair. The findings suggest that miR133 may be a lynchpin in the development of heart disease, which may pinpoint new therapeutic targets in the pathway."
Notes to editors
Publication details: Mutual antagonism between IP3RII and miRNA-133a regulates calcium signals and cardiac hypertrophy Drawnel, F.M., et al 2012. J. Cell Biol. doi:10.1083/jcb.201111095.
About the Babraham Institute
The Babraham Institute, which receives strategic funding (£22.4M in 2010-11) from the Biotechnology and Biological Sciences Research Council (BBSRC), undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute's research provides greater understanding of the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. www.babraham.ac.uk
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