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Department of Medicine and Department of Pharmacology, University of California, San Diego, and Department of Medicine, Department of Veterans Affairs Medical Center, La Jolla, California 92093
The
force-frequency relationship (FFR) describes the frequency-dependent
potentiation of cardiac contractility. The interaction of the
sarcoplasmic reticulum
Ca2+-adenosinetriphosphatase
(SERCA2) with its inhibitory protein phospholamban (PLB) might be
involved in the control of the FFR. The FFR was analyzed in two systems
in which the PLB-to-SERCA2 ratio was modulated. Adult rabbit cardiac
myocytes were transduced with adenovirus encoding for SERCA2, PLB, and
-galactosidase (control). After 3 days, the relative PLB/SERCA2
values were significantly different between groups (SERCA2, 0.5;
control, 1.0; PLB, 4.5). SERCA2 overexpression shortened relaxation by
23% relative to control, whereas PLB prolonged relaxation by 39% and
reduced contractility by 47% (0.1 Hz). When the stimulation frequency
was increased to 1.5 Hz, myocyte contractility was increased by 30% in
control myocytes. PLB-overexpressing myocytes showed an augmented
positive FFR (+78%), whereas SERCA2-transduced myocytes displayed a
negative FFR (
15%). A more negative FFR was also found in
papillary muscles from SERCA2 transgenic mice. These findings
demonstrate that the ratio of phospholamban to SERCA2 is an
important component in the control of the FFR.
sarcoplasmic reticulum; staircase; contractility; adenovirus; sarcoplasmic reticulum calcium-adenosinetriphosphatase
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