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(Circulation Research. 2005;97:457.)
© 2005 American Heart Association, Inc.

Cellular Biology

Paradoxical Cellular Ca²⁺ Signaling in Severe but Compensated Canine Left Ventricular Hypertrophy

Long-Sheng Song, YeQing Pi, Song-Jung Kim, Atsuko Yatani, Silvia Guatimosim, Raymond K. Kudej, Qingxiu Zhang, Heping Cheng, Luc Hittinger, Bijan Ghaleh, Dorothy E. Vatner, W. Jonathan Lederer, Stephen F. Vatner

From the Department of Cell Biology and Molecular Medicine and the Cardiovascular Research Institute (Y.Q.P., S.-J.K., A.Y., R.K.K., Q.Z., L.H., B.G., D.E.V., S.F.V.), University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark; the Medical Biotechnology Center (L.-S.S., S.G., W.J.L.) University of Maryland Biotechnology Institute, Baltimore; the Department of Physiology and Biophysics (S.G.), Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; and the Laboratory of Cardiovascular Science (H.C.), National Institute on Aging, National Institutes of Health, Baltimore, Md.

Correspondence to Dr Stephen F. Vatner, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 S Orange Ave, MSB G609, Newark, NJ 07103. E-mail vatnersf{at}umdnj.edu; or Dr W. Jonathan Lederer, Medical Biotechnology Center, University of Maryland Biotech Institute, 725 W Lombard St, Baltimore, MD 21201. E-mail: lederer@umbi.umd.edu

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 (I_Ca) density but the ability of I_Ca 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.

Key Words: hypertrophy • Ca²⁺ sparks • E-C coupling • myocyte contractility • Ca²⁺ handling

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