Paradoxical cellular Ca2+ signaling in severe but compensated canine left ventricular hypertrophy.
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.
Song
Long-Sheng
LS
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.
Pi
Yeqing
Y
Kim
Song-Jung
SJ
Yatani
Atsuko
A
Guatimosim
Silvia
S
Kudej
Raymond K
RK
Zhang
Qingxiu
Q
Cheng
Heping
H
Hittinger
Luc
L
Ghaleh
Bijan
B
Vatner
Dorothy E
DE
Lederer
W Jonathan
WJ
Vatner
Stephen F
SF
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
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium