title: Paradoxical cellular Ca2+ signaling in severe but compensated canine left ventricular hypertrophy.
abstract: In conscious dogs with severe left ventricular (LV) hypertrophy (H) (doubling of LV/body weight), which developed gradually over 1 to 2 years after aortic banding, baseline LV function was well compensated. The LV was able to generate twice the LV systolic pressure without an increase in LV end-diastolic pressure, or decrease in LV dP/dt or LV wall thickening. However, LV myocytes isolated from LVH dogs exhibited impaired contraction at baseline and in response to Ca2+. There was no change in L-type Ca2+ channel current (ICa) density but the ability of ICa to trigger Ca2+ release from the sarcoplasmic reticulum (SR) was reduced. Immunoblot analysis revealed a 68% decrease in SERCA2a, and a 35% decrease in the number of ryanodine receptors (RyR2), with no changes in protein level of calsequestrin, Na+/Ca2+ exchanger or phospholamban (PLB), but with both RyR2 and PLB hyperphosphorylated. Spontaneous Ca2+ sparks in LVH cells were found to have prolonged duration but similar intensities despite the reduced SR Ca2+ load. A higher Ca2+ spark rate was observed in LVH cells, but this is inconsistent with the reduced SR Ca2+ content. However, Ca2+ waves were found to be less frequent, slower and were more likely to be aborted in Ca2+-challenged LVH cells. These paradoxical observations could be accounted for by a nonuniform SR Ca2+ distribution, RyR2 hyperphosphorylation in the presence of decreased global SR Ca2+ load. We conclude that severe LVH with compensation masks cellular and subcellular Ca2+ defects that remain likely contributors to the limited contractile reserve of LVH.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.forename: Yeqing
authors.initials: Y
authors.lastname: Pi
authors.forename: Song-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Atsuko
authors.initials: A
authors.lastname: Yatani
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
authors.forename: Raymond K
authors.initials: RK
authors.lastname: Kudej
authors.forename: Qingxiu
authors.initials: Q
authors.lastname: Zhang
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.forename: Luc
authors.initials: L
authors.lastname: Hittinger
authors.forename: Bijan
authors.initials: B
authors.lastname: Ghaleh
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.forename: W Jonathan
authors.initials: WJ
authors.lastname: Lederer
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D000252:Calcium-Transporting ATPases / Q000032:analysis; D003971:Diastole; D004285:Dogs; D005260:Female; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D016277:Ventricular Function, Left
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium