Published online before print May 19, 2005, doi: 10.1161/01.RES.0000170652.71414.16
© 2005 American Heart Association, Inc.
Integrative Physiology |
Molecular and Functional Signature of Heart Hypertrophy During Pregnancy
From the Department of Anesthesiology (M.E., R.D., A.A., T.Y.M., H.R., Y.W., L.T., E.S.), Division of Molecular Medicine, Department of Molecular and Medical Pharmacology (L.T.), Department of Physiology (E.S.), Department of Medicine (Y.W.) and Brain Research Institute (L.T., E.S.), David Geffen School of Medicine at the University of California Los Angeles.
Correspondence to Dr Enrico Stefani, UCLA School of Medicine, Department of Anesthesiology, BH-520A CHS, Box 957115, Los Angeles, CA 90095-7115. E-mail estefani{at}ucla.edu
During pregnancy, the heart develops a reversible physiological hypertrophic growth in response to mechanical stress and increased cardiac output; however, underlying molecular mechanisms remain unknown. Here, we investigated pregnancy-related changes in heart structure, function, and gene expression of known markers of pathological hypertrophy and cell stretching in mice hearts. In late pregnancy, hearts show eccentric hypertrophy, as expected for a response to volume overload, with normal left ventricular diastolic function and a moderate reduction in systolic function. Pregnancy-related physiological heart hypertrophy does not induce expression changes of known markers of pathological hypertrophy like: 
- and ß-myosin heavy chain, atrial natriuretic factor, phospholamban, and sarcoplasmic reticulum Ca2+-ATPase. Instead, it induces the remodeling of Kv4.3 channel and increased c-Src tyrosine kinase activity, a stretch-responsive kinase. Cardiac Kv4.3 channel gene expression was downregulated by 
3- to 5-fold, both at the mRNA and protein levels, and was paralleled by a reduction in transient outward K+ currents, a longer action potential and by prolongation of the QT interval. Downregulation of cardiac Kv4.3 transcripts was mimicked by estrogen treatment in ovariectomized mice, and was prevented by the estrogen receptor antagonist ICI 182,780. c-Src activity increased by 2-fold in late pregnancy and after estrogen treatment. We propose that, in addition to mechanical stress, the rise of estrogen toward the end of pregnancy contributes to pregnancy-related heart hypertrophy by increased c-Src activity and that the rise of estrogen is one factor that down regulates cardiac Kv4.3 gene expression providing a molecular correlate for a longer QT interval in pregnancy.
Key Words: heart hypertrophy • pregnancy • estrogen • Ito • Kv4.3 channel
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