Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure.
As a critical step toward understanding the role of abnormal intracellular Ca(2+) release via the ryanodine receptor (RyR(2)) 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 RyR(2) hyperphosphorylated at Ser(2808)? 2) Does the spatial distribution of RyR(2) clusters change in failing hearts? Using a newly developed semiquantitative immunohistochemistry method and Western blotting, we measured phosphorylation of RyR(2) at Ser(2808) in the spontaneously hypertensive rat (SHR) at four distinct disease stages. A major finding is that hyperphosphorylation of RyR(2) at Ser(2808) occurred only at late-stage heart failure in SHR, but not in age-matched controls. Furthermore, the spacing between RyR(2) clusters was shortened in failing hearts, as predicted by quantitative model simulation to increase spontaneous Ca(2+) wave generation and arrhythmias.
Chen-Izu
Ye
Y
Dept. of Internal Medicine, Univ. of Kentucky College of Medicine, 741 S. Limestone St., BBSRB, Rm. B255, Lexington, KY 40536-0509, USA. YeChen-Izu@uky.edu
Ward
Christopher W
CW
Stark
Wayne
W
Banyasz
Tamas
T
Sumandea
Marius P
MP
Balke
C William
CW
Izu
Leighton T
LT
Wehrens
Xander H T
XH
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000150:complications / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D003198:Computer Simulation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006973:Hypertension / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008955:Models, Cardiovascular; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015203:Reproducibility of Results; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012694:Serine / Q000378:metabolism
D019837:Ryanodine Receptor Calcium Release Channel; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium