Phosphorylation of RyR2and shortening of RyR2cluster spacing in spontaneously hypertensive rat with heart failure

Abstract

As a critical step toward understanding the role of abnormal intracellular Ca2+release via the ryanodine receptor (RyR2) during the development of hypertension-induced cardiac hypertrophy and heart failure, this study examines two questions: 1) At what stage, if ever, in the development of hypertrophy and heart failure is RyR2hyperphosphorylated at Ser2808? 2) Does the spatial distribution of RyR2clusters change in failing hearts? Using a newly developed semiquantitative immunohistochemistry method and Western blotting, we measured phosphorylation of RyR2at Ser2808in the spontaneously hypertensive rat (SHR) at four distinct disease stages. A major finding is that hyperphosphorylation of RyR2at Ser2808occurred only at late-stage heart failure in SHR, but not in age-matched controls. Furthermore, the spacing between RyR2clusters was shortened in failing hearts, as predicted by quantitative model simulation to increase spontaneous Ca2+wave generation and arrhythmias.