Journal Article

Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na<sup>+</sup>–Ca<sup>2+</sup> exchanger to α-linolenic acid

Bradley P. Ander, Cecilia Hurtado, Carla S. Raposo, Thane G. Maddaford, Justin F. Deniset, Larry V. Hryshko, Grant N. Pierce and Anton Lukas

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 73, issue 2, pages 395-403
Published in print January 2007 | ISSN: 0008-6363
Published online January 2007 | e-ISSN: 1755-3245 | DOI: http://dx.doi.org/10.1016/j.cardiores.2006.09.013
Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na+–Ca2+ exchanger to α-linolenic acid

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Abstract

Objective: Dietary intake of ω-3 polyunsaturated fatty acids (PUFA) like α-linolenic acid (ALA) is antiarrhythmic and cardioprotective. PUFA may also be beneficial in hypertension. Altered Na+–Ca2+ exchanger (NCX) activity has been implicated in arrhythmias, hypertension and heart failure and may be a target for PUFA. Thus, we tested the effects of ALA and other distinct fatty acids on the cardiac (NCX1.1) and vascular (NCX1.3) NCX isoforms.

Methods: HEK293 cells stably expressing NCX isoforms were ramped from +60 to −100 mV (over 1600 ms) in the absence and presence of 25 μM oleic acid (OA, ω-9), linoleic acid (LA, ω-6), ALA (ω-3), or eicosapentaenoic acid (EPA, ω-3). NiCl2 (5 mM) was used to inhibit and therefore identify the NCX current. The effect of 25 μM ALA on NCX1.1 and NCX1.3 activity was also assessed in adult rat ventricular cardiomyocytes and rabbit aortic vascular smooth muscle cells (VSMC) by measuring [Ca2+]i following substitution of [Na+]o with Li+.

Results: Application of Ni2+ had no effect in non-transfected cells. ALA and EPA (25 μM) reduced the Ni2+-sensitive forward NCX1.1 current (at −100 mV) by 64% and reverse current (at +60 mV) by 57%, and inhibited the Ni2+-sensitive NCX1.3 forward and reverse currents by 79% and 76%, respectively. Neither OA nor LA (25 μM) affected the NCX1.1 currents, but both partially inhibited the forward and reverse mode NCX1.3 currents. Inhibition of NCX1.3 by ALA occurred at a much lower IC50 (∼19 nM) than for NCX1.1 (∼120 nM). In cardiomyocytes and VSMC, ALA significantly reduced the Li+-induced rise in intracellular [Ca2+].

Conclusions: NCX1.3 is more sensitive to inhibition by ALA than NCX1.1. In addition, only ω-3 PUFA inhibits NCX1.1, but several classes of fatty acids inhibit NCX1.3. The differential sensitivity of NCX isoforms to fatty acids may have important implications as therapeutic approaches for hypertension, heart failure and arrhythmias.

Keywords: Na/Ca-exchanger; Hypertension; Ion exchangers; Antihypertensive agents; Antiarrhythmic agents

Journal Article.  4991 words.  Illustrated.

Subjects: Cardiovascular Medicine

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