NDLI: Regional genomic regulation of cardiac sodium

Content Provider	PubMed Central
Author	Chen, Guojun Yang, Xiaoyan Alber, Sean Shusterman, Vladimir Salama, Guy
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 (I Ca,L) at the base of the heart. In principle, higher Ca2+ influx via I Ca,L should be balanced by higher efflux, perhaps mediated by parallel sex differences of sodium–calcium exchange (NCX) current (I NCX). 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) I NCX 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 I NCX was measured on days 0, 1, 2 and 3. Inward and outward I NCX decreased over 2 days in female base myocytes becoming similar to I NCX at the apex. E2 incubation (24 h) increased NCX1 (50%) and I NCX (∼3-fold at 60 mV) in female base but not endocardium, apex or in male base myocytes. I NCX 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 I Kr 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 I NCX 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.
Related Links	http://dx.doi.org/10.1113/jphysiol.2010.203398
Ending Page	1080
Page Count	20
Starting Page	1061
File Format	PDF
ISSN	00223751
e-ISSN	14697793
Journal	The Journal of Physiology
Issue Number	Pt 5
Volume Number	589
Language	English
Publisher	Blackwell Science Inc
Publisher Date	2011-03-01
Access Restriction	Open
Rights Holder	Blackwell Science Inc
Subject Keyword	Physiology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology Sports Science

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