AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol 293: H2409-H2417, 2007. First published July 13, 2007; doi:10.1152/ajpheart.00562.2007
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Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure

Ye Chen-Izu,1 Christopher W. Ward,2 Wayne Stark, Jr.,3 Tamas Banyasz,1,4 Marius P. Sumandea,1 C. William Balke,1 Leighton T. Izu,1 and Xander H. T. Wehrens5

1Departments of Internal Medicine and Physiology, University of Kentucky College of Medicine, Lexington, Kentucky; 2School of Nursing and 3School of Medicine, University of Maryland, Baltimore, Maryland; 4Department of Physiology, University Medical School of Debrecen, Debrecen, Hungary; and 5Departments of Molecular Physiology and Biophysics, and Medicine (Cardiology), Baylor College of Medicine, Houston, Texas

Submitted 14 May 2007 ; accepted in final form 11 July 2007

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 RyR2 hyperphosphorylated at Ser2808? 2) Does the spatial distribution of RyR2 clusters change in failing hearts? Using a newly developed semiquantitative immunohistochemistry method and Western blotting, we measured phosphorylation of RyR2 at Ser2808 in the spontaneously hypertensive rat (SHR) at four distinct disease stages. A major finding is that hyperphosphorylation of RyR2 at Ser2808 occurred only at late-stage heart failure in SHR, but not in age-matched controls. Furthermore, the spacing between RyR2 clusters was shortened in failing hearts, as predicted by quantitative model simulation to increase spontaneous Ca2+ wave generation and arrhythmias.

ryanodine receptor; hypertension; cardiac hypertrophy; protein kinase A; spontaneously hypertensive rat



Address for reprint requests and other correspondence: Y. Chen-Izu, Dept. of Internal Medicine, Univ. of Kentucky College of Medicine, 741 S. Limestone St., BBSRB, Rm. B255, Lexington, KY 40536-0509 (e-mail: YeChen-Izu{at}uky.edu)







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