Published online before print August 12, 2004, doi: 10.1161/01.RES.0000142316.08250.68
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Submitted on April 23, 2004
Revised on August 2, 2004
Accepted on August 3, 2004
Functional Adult Myocardium in the Absence of Na+-Ca2+ Exchange. Cardiac-Specific Knockout of NCX1
Scott A. Henderson ;
From the Departments of Physiology and Medicine and the Cardiovascular Research Laboratories (S.A.H., J.S., T.H., C.M., C.C., D.A.N., M.J., K.P.R., J.S.F., R.R., J.I.G., K.D.P.), David Geffen School of Medicine at the University of California, Los Angeles; and the Department of Cell Biology (M.R., M.F.), The Scripps Research Institute, La Jolla, Calif. Present affiliation for R.S.R. is the Department of Medicine, University of California, San Diego School of Medicine.
* To whom correspondence should be addressed. E-mail: kphilipson{at}mednet.ucla.edu.
The excitation-contraction coupling cycle in cardiac muscle is initiated by an influx of Ca2+ through voltage-dependent Ca2+ channels. Ca2+ influx induces a release of Ca2+ from the sarcoplasmic reticulum and myocyte contraction. To maintain Ca2+ homeostasis, Ca2+ entry is balanced by efflux mediated by the sarcolemmal Na+-Ca2+ exchanger. In the absence of Na+-Ca2+ exchange, it would be expected that cardiac myocytes would overload with Ca2+. Using Cre/loxP technology, we generated mice with a cardiac-specific knockout of the Na+-Ca2+ exchanger, NCX1. The exchanger is completely ablated in 80% to 90% of the cardiomyocytes as determined by immunoblot, immunofluorescence, and exchange function. Surprisingly, the NCX1 knockout mice live to adulthood with only modestly reduced cardiac function as assessed by echocardiography. At 7.5 weeks of age, measures of contractility are decreased by 20% to 30%. We detect no adaptation of the myocardium to the absence of the Na+-Ca2+ exchanger as measured by both immunoblots and microarray analysis. Ca2+ transients of isolated myocytes from knockout mice display normal magnitudes and relaxation kinetics and normal responses to isoproterenol. Under voltage clamp conditions, the current through L-type Ca2+ channels is reduced by 50%, although the number of channels is unchanged. An abbreviated action potential may further reduce Ca2+ influx. Rather than upregulate other Ca2+ efflux mechanisms, the myocardium appears to functionally adapt to the absence of the Na+-Ca2+ exchanger by limiting Ca2+ influx. The magnitude of Ca2+ transients appears to be maintained by an increased gain of sarcoplasmic reticular Ca2+ release. The myocardium of the NCX1 knockout mice undergoes a remarkable adaptation to maintain near normal cardiac function.
Key words: Na+-Ca2+ exchange • excitation-contraction coupling • genetically altered mice
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