Highlight Publication June 2009

Dagmar Harzheim, Mehregan Movassagh, Roger Foo, Oliver Ritter, Aslam Tashfeen, Stuart Conway,
Martin Bootman, and Llewelyn Roderick
Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2+ transients and arrhythmias associated with cardiac hypertrophy
PNAS 2009 106:11406-11411; published online before print June 23, 2009
http://dx.doi.org/10.1073/pnas.0905485106

Lay Summary

Cardiovascular disease is a major cause of mortality causing a third of all deaths. Contributing to this statistic is death arising due to cardiac failure, which occurs when the action of the heart can no longer meet the cardiovascular requirements of the organism. In many cases, cardiac failure is preceded by hypertrophy, which can simply be described as a growth in the size of the muscle cells of the heart. Precipitating factors for cardiac hypertrophy include high blood pressure and coronary heart disease. Although cardiac hypertrophy is initially an adaptive response to the increased workload placed on the heart, which enhances cardiac function, during later stages of hypertrophy, prior to failure, cardiac output is decreased. A further risk factor associated with hypertrophy is cardiac arrhythmia, which can lead to sudden cardiac death. Contributing to the increase in cardiac function during the early stages of hypertrophy is an increase in the magnitude of the intracellular calcium fluxes that trigger myocyte contraction. Hypertrophic myocytes also exhibit an increased occurrence in spontaneous increases in intracellular calcium that may precipitate arrhythmia.

Our data show that both the enhancement of calcium fluxes and the spontaneous arrhythmogenic calcium signals associated with hypertrophy are mediated by an increase in the expression of the inositol 1,4,5-trisphosphate receptor (InsP3R) intracellular calcium release channel. These channels are localised on membrane-bound intracellular calcium stores including the sarcoplasmic reticulum and endoplasmic reticulum. Interestingly, InsP3R expression was not homogeneously elevated throughout the myocyte. Rather, its expression was specifically increased in regions of the cell where ryanodine receptors are expressed. Ryanodine receptors are the major calcium release channels of cardiac myocytes responsible for the calcium fluxes that mediate contraction, which under normal conditions outnumber InsP3Rs by ~ 100:1. Our data show that by sensitising calcium release through ryanodine receptors, these relatively few InsP3Rs have a major impact on cardiac calcium handling. Specifically, they underlie an enhancement in the action-potential associated calcium release through the ryanodine receptors thus causing greater contraction. Moreover, as ryanodine receptors are activated by calcium, increased calcium fluxes via InsP3Rs cause an increase in frequency in spontaneous openings of ryanodine receptors, which may underlie arrhythmogenic calcium signals.

These data clearly define a molecular mechanism underlying both beneficial and pathological modifications in calcium handling in cardiac myocytes isolated from hypertrophic hearts taken from spontaneously hypertensive rats. In collaboration with scientists at Addenbrookes we also determined that InsP3R expression was increased in hearts from human patients with heart failure. Together our findings illustrate the importance of InsP3Rs in pathology and suggest that they represent an important target for therapeutic intervention.

About the lead  author

Dagmar Harzheim joined the Calcium Group at the Babraham Institute in 2007 after completing her PhD and a postdoctoral training at the University of Cologne and the Research Centre Juelich, Germany, studying cardiac pacemaker mechanisms. In Babraham, Dagmar worked on the role of Ca2+ release through InsP3Rs in the heart, in particular during cardiac hypertrophy.

This work is supported by the British Heart Foundation.