title: Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure.
abstract: 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.
authors.affiliation: 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
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen-Izu
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ward
authors.forename: Wayne
authors.initials: W
authors.lastname: Stark
authors.forename: Tamas
authors.initials: T
authors.lastname: Banyasz
authors.forename: Marius P
authors.initials: MP
authors.lastname: Sumandea
authors.forename: C William
authors.initials: CW
authors.lastname: Balke
authors.forename: Leighton T
authors.initials: LT
authors.lastname: Izu
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: 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
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium