Submitted on May 14, 2007
Accepted on July 11, 2007
Phosphorylation of RyR2 and shortening of RyR2 cluster spacing
in spontaneously hypertensive rat with heart failure
Ye Chen-Izu1*, Christopher W Ward2, Wayne Stark Jr.3, Tamas Banyasz4, Marius P. Sumandea1, C. William Balke5, Leighton T Izu1, and Xander H.T. Wehrens6
1 Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States
2 Schools of Nursing, University of Maryland Baltimore, Baltimore, Maryland, United States
3 Medicine, University of Maryland Baltimore, Baltimore, Maryland, United States
4 Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States; Physiology, University Medical School of Debrecen, Debrecen, Hungary
5 Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States; Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States
6 Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States
* To whom correspondence should be addressed. E-mail: YeChen-Izu{at}uky.edu.
As a critical step towards 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-Ser2808 hyperphosphorylated? (2) Does the spatial distribution of RyR2 clusters change in failing hearts? We measured phosphorylation of RyR2-Ser2808 in the spontaneously hypertensive rat (SHR), using a newly developed semi-quantitative immunohistochemistry method and Western blotting. A major finding is that hyperphosphorylation of RyR2-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, which is predicted by quantitative model simulation to increase spontaneous Ca2+ wave generation and arrhythmias.
