title: Molecular and functional signature of heart hypertrophy during pregnancy.
abstract: 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: alpha- and beta-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 approximately 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 approximately 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.
authors.affiliation: Department of Anesthesiology, David Geffen School of Medicine, University of California Los Angeles, CA 90095-7115, USA.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Eghbali
authors.forename: Rupal
authors.initials: R
authors.lastname: Deva
authors.forename: Abderrahmane
authors.initials: A
authors.lastname: Alioua
authors.forename: Tamara Y
authors.initials: TY
authors.lastname: Minosyan
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ruan
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: Ligia
authors.initials: L
authors.lastname: Toro
authors.forename: Enrico
authors.initials: E
authors.lastname: Stefani
mesh_terms: D000200:Action Potentials; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D004452:Echocardiography; D004562:Electrocardiography; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D015221:Potassium Channels / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000032:analysis / Q000235:genetics; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051672:Shal Potassium Channels; D016277:Ventricular Function, Left; D019061:src-Family Kinases
chemical_list: D004967:Estrogens; C497022:Kcnd3 protein, mouse; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D000077267:Fulvestrant; D004958:Estradiol; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases