Research lead
Scientists at the Babraham Institute, Cambridge, have identified a signalling process involved in the development of hypertrophy, or thickening of the heart muscle, paving the way for new treatments for cardiac hypertrophy.
Using a combination of imaging and genetic manipulation techniques the researchers have shown that the changes in calcium signalling that result in hypertrophy occur in the nucleus of the cell. These nuclear calcium signals are 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 inositol 1,4,5-trisphosphate, IP3, which is produced after the binding of the hormone 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.
The researchers found stimuli other than endothelin also induced hypertrophy via the IP3-calcium-NFAT pathway. These stimuli, such as adrenalin, act by causing endothelin to be secreted from cardiac myocytes. This 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 Llewelyn Roderick, who led the research. “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.”
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