IP3 Receptor Linked to Cardiac Hypertrophy

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Cardiac hypertrophy is a thickening of the heart muscle – characterized by increased cell size rather than number – in response to conditions such as high blood pressure and coronary heart disease, which results in a decrease in size of the chambers of the heart, including the left and right ventricles. Since hypertrophy is associated with heart failure, irregular heart rhythms and an increased risk of angina and heart attack, understanding the mechanisms underlying this abnormal thickening is of great importance. Scientists at the Babraham Institute have now identified a new signalling process in the heart which contributes to cardiac hypertrophy. Rhythmical Ca2+ increases are fundamental to contraction of the heart muscle, but elevated Ca2+ levels also regulate the gene transcription that leads to hypertrophy. The Babraham team found that it is localised increases in Ca2+ concentrations in the cell nucleus that activate the genes responsible for hypertrophy. These nuclear Ca2+ signals, which are distinct from the Ca2+ signals that control the rhythmical contractions of the heart, were found to be generated by opening of the inositol 1,4,5-trisphosphate (IP3) receptor calcium channels (IP3Rs) which surround the nucleus.

IP3 receptor structure
These channels open in response to the increased cellular levels of IP3 that are generated on binding of the vasoconstricting peptide, endothelin-1, to receptors on the surface of cardiac myocytes. Nuclear factor of activated T cells (NFAT), which is known to regulate genes involved in pathological hypertrophy, was shown to be activated by these IP3-mediated increases in nuclear Ca2+ levels and not by the Ca2+ signals associated with contraction. The study confirms the importance of the endothelin pathway in cardiac hypertrophy and provides evidence that modulation of IP3 signalling would be a suitable target for future therapies.

The study is published in the journal Molecular Cell.

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