Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na+-Ca2+ exchanger to α-linolenic acid

Objective: Dietary intake of omega-3 polyunsaturated fatty acids (PUFA) like alpha-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 (NCX 1.1) and vascular (NCX 1.3) 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 mu M oleic acid (OA, omega-9), linoleic acid (LA, omega-6), ALA (omega-3), or eicosapentaenoic acid (EPA, omega-3). NiCl2 (5 mM) was used to inhibit and therefore identify the NCX current. The effect of 25 mu M ALA on NCX 1.1 and NCX 1.3 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 mu M) reduced the Ni2+-sensitive forward NCX 1.1 current (at -100 mV) by 64% and reverse current (at +60 mV) by 57%, and inhibited the Ni2+-sensitive NCX 1.3 forward and reverse currents by 79% and 76%, respectively. Neither OA nor LA (25 mu M) affected the NCX 1.1 currents, but both partially inhibited the forward and reverse mode NCX 1.3 currents. Inhibition of NCX 1.3 by ALA occurred at a much lower IC50 (similar to 19 nM) than for NCX 1.1 (similar to 120 nM). In cardiomyocytes and VSMC, ALA significantly reduced the Li+-induced rise in intracellular [Ca2+]. Conclusions: NCX 1.3 is more sensitive to inhibition by ALA than NCX 1.1. In addition, only omega-3 PUFA inhibits NCX 1.1, but several classes of fatty acids inhibit NCX 1.3. The differential sensitivity of NCX isoforms to fatty acids may have important implications as therapeutic approaches for hypertension, heart failure and arrhythmias. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.