Molecular and Functional Signature of Heart Hypertrophy During Pregnancy

• Published in: Circulation research Vol. 96; no. 11; pp. 1208 - 1216
• Main Authors: Eghbali, Mansoureh, Deva, Rupal, Alioua, Abderrahmane, Minosyan, Tamara Y, Ruan, Hongmei, Wang, Yibin, Toro, Ligia, Stefani, Enrico
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 10.06.2005; Lippincott
• Subjects: Action Potentials; Animals; Biological and medical sciences; Cardiomegaly - etiology; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Echocardiography; Electrocardiography; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogens - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Mice; Mice, Inbred C57BL; Myocardium - pathology; Potassium Channels - physiology; Potassium Channels, Voltage-Gated - analysis; Potassium Channels, Voltage-Gated - genetics; Pregnancy; Pregnancy Complications, Cardiovascular - etiology; Pregnancy Complications, Cardiovascular - pathology; Pregnancy Complications, Cardiovascular - physiopathology; Protein-Tyrosine Kinases - metabolism; Shal Potassium Channels; src-Family Kinases; Ventricular Function, Left; Vertebrates: cardiovascular system; Heart; Pregnancy; heart hypertrophy; Vertebrata; Mammalia; Ito; Estrogen; Circulatory system; Sex steroid hormone; Ovarian hormone; Hypertrophy; Kv4.3 channel
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000170652.71414.16

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 likeα- and β-myosin heavy chain, atrial natriuretic factor, phospholamban, and sarcoplasmic reticulum Ca-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.