Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen

Guojun Chen; Xiaoyan Yang; Sean Alber; Vladimir Shusterman; Guy Salama

doi:10.1113/jphysiol.2010.203398

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Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen

Journal article

Open access

Peer reviewed

Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen

Guojun Chen, Xiaoyan Yang, Sean Alber, Vladimir Shusterman and Guy Salama

The Journal of physiology, Vol.589(Pt 5), pp.1061-1080

03/01/2011

DOI: 10.1113/jphysiol.2010.203398

PMCID: PMC3060587

PMID: 21224239

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Abstract

Female rabbit hearts are more susceptible to torsade de pointes (TdP) in acquired long QT type 2 than males, in-part due to higher L-type Ca2+ current (ICa,L) at the base of the heart. In principle, higher Ca2+ influx via ICa,L should be balanced by higher efflux, perhaps mediated by parallel sex differences of sodium-calcium exchange (NCX) current (INCX). We now show that NCX1, like Cav1.2α, is greater at the base of female than male left ventricular epicardium and greater at the base than at the apex in both sexes. In voltage-clamp studies, inward (0, +20 mV, P < 0.04) and outward (-80, -60, -40, -20 mV, P < 0.01) INCX densities were significantly higher (1.5-2 fold) in female base compared to apex and male (base and apex) myocytes. Myocytes were incubated ±17β-oestradiol (E2 = 1 nm) and INCX was measured on days 0, 1, 2 and 3. Inward and outward INCX decreased over 2 days in female base myocytes becoming similar to INCX at the apex. E2 incubation (24 h) increased NCX1 (50%) and INCX (∼3-fold at 60 mV) in female base but not endocardium, apex or in male base myocytes. INCX upregulation by E2 was blunted by an oestrogen receptor (ER) antagonist (fulvestrant, 1 μm), and inhibition of transcription (actinomycin D, 5 μg ml-1) or translation (cycloheximide, 20 μg ml-1). Dofetilide (an IKr blocker) induced early afterdepolarizations (EADs) in female base myocytes cultured for 1 day if incubated with E2, but not without E2 or with E2+KB-R4973 (an INCX inhibitor), E2+fulvestrant or E2 with apex myocytes. Thus, E2 upregulates NCX1 by a genomic mechanism mediated by ERs, and de novo mRNA and protein biosynthesis, in a sex- and region-dependent manner which contributes to the enhanced propensity to EADs and TdP in female hearts.

Immunohistochemistry

Electrophysiology

Rabbits

Estradiol - analogs & derivatives

Estrogens - pharmacology

Phenethylamines - pharmacology

Myocytes, Cardiac - cytology

Estrogen Antagonists - pharmacology

Male

Sulfonamides - pharmacology

Blotting, Western

Cycloheximide - pharmacology

Myocardium - cytology

Animals

Myocytes, Cardiac - drug effects

Sodium-Calcium Exchanger - metabolism

Myocardium - metabolism

Heart - drug effects

Myocytes, Cardiac - metabolism

Female

Protein Synthesis Inhibitors - pharmacology

Dactinomycin - pharmacology

Estradiol - pharmacology

Details

Title: Subtitle: Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen
Creators: Guojun Chen - University of Pittsburgh, School of Medicine, Cardiovascular Institute, 3550 Terrace Street, Suite S 628 Scaife Hall, Pittsburgh, PA 15261, USA
Xiaoyan Yang
Sean Alber
Vladimir Shusterman
Guy Salama
Resource Type: Journal article
Publication Details: The Journal of physiology, Vol.589(Pt 5), pp.1061-1080
DOI: 10.1113/jphysiol.2010.203398
PMID: 21224239
PMCID: PMC3060587
NLM abbreviation: J Physiol
ISSN: 0022-3751
eISSN: 1469-7793
Grant note: R01 HL057929 / NHLBI NIH HHS R01 HL070722 / NHLBI NIH HHS HL57929 / NHLBI NIH HHS HL70722 / NHLBI NIH HHS
Language: English
Date published: 03/01/2011
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984094363902771

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