New Insights From Cellular Signals Pinpoint A Therapeutic Target To Tackle Cardiovascular Disease

As hypertrophy can lead to debilitating heart failure, and diseases of the cardiovascular system (heart and blood vessels) are responsible for about one third of all deaths in the western world, understanding the cellular signals behind this aberrant growth of the heart is vitally important. This discovery, reported in the scientific journal Molecular Cell, potentially paves the way for innovative treatments to tackle cardiac hypertrophy.

“Until recently, it was considered that disease-induced changes in the shape of calcium increases in heart cells switched on genes that controlled hypertrophic growth,” explained Dr Llewelyn Roderick, leading the research team. “We have found, however, that localised calcium increases in the cell nucleus, which are quite separate from the large increases in cellular calcium responsible for general contraction of heart cells, activate hypertrophic genes. In this way, cardiac myocytes control their own destiny; it’s just a matter of location, location, location.”  

Funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and The British Heart Foundation, the combined use of sophisticated imaging and genetic manipulation techniques has revealed that the changes in calcium signalling that result in hypertrophy occur in the nucleus of the cell. These nuclear calcium signals are ‘special’ and distinct from the electrically-evoked calcium signals controlling the regular contraction of the heart.

The nuclear calcium signals are generated following the opening of inositol 1,4,5-trisphosphate receptor calcium channels (IP3Rs), which surround the nucleus. These channels open when they sense an increase in the cellular levels of a chemical messenger called inositol 1,4,5-trisphosphate, IP3, which is produced after the binding of a hormone called endothelin to its receptors on the surface of cardiac myocytes (heart muscle cells). Significantly, a molecule called NFAT, known to regulate genes involved in pathological hypertrophy, was activated by these IP3-mediated increases in nuclear calcium and not as previously thought by the calcium signals associated with contraction.  

In this study, the authors found stimuli other than endothelin also induced hypertrophy via the IP3-calcium-NFAT pathway. They showed that these stimuli, such as adrenalin (the fight or flight hormone), act by causing endothelin to be secreted from cardiac myocytes. This secreted endothelin then induces IP3-dependent calcium release in the same cells from which the endothelin was originally secreted. As endothelin levels are higher in patients with heart disease and inhibition of endothelin signalling has been reported to have certain beneficial effects, this finding has significant relevance to human disease. 

 “We have uncovered a new cellular signalling loop that is key to regulating many forms of cardiac hypertrophy, said Dr Roderick. “This discovery has great clinical significance, supporting the notion that the endothelin pathway is a good target for pharmacological intervention and that intervening in inositol 1,4,5-trisphosphate signalling would be a suitable target for the development of future therapies. “  

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation commented, "Levels of calcium inside heart muscle cells must rapidly change to allow them to contract and relax with every heart beat. However, changes in calcium can also alter heart muscle cell structure in response to injury, such as after a heart attack, and potentially lead to hypertrophy and heart failure. It is vital to understand how hypertrophy develops and until now, researchers have not understood how these two different actions of calcium inside the cell are separately controlled.”

“This excellent piece of work from the Babraham Institute has used cutting-edge imaging techniques to show that the location in the cell where these calcium changes take place is crucial. They have shown for the first time that the calcium changes leading to hypertrophy only take place in the nucleus of the cell. They have also discovered the molecular pathways which control this rise in calcium in the nucleus. This is vitally important research to understand how cardiac hypertrophy develops and the discovery of these pathways may provide clues to guide the development of new drugs to prevent this condition."