Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na+-Ca2+ exchanger to α-linolenic acid
Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na+-Ca2+ exchanger to α-linolenic acid
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DOI：
10.1016/j.cardiores.2006.09.013
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发表时间：
2007-01-15
影响因子：
10.8
通讯作者：
Lukas, Anton
中科院分区：
文献类型：
--
作者：
Ander, Bradley P.;Hurtado, Cecilia;Lukas, Anton
目的：膳食摄入欧米茄-3多不饱和脂肪酸(PUFA)类α-亚麻酸(ALA)具有抗心律失常和心脏保护作用。多不饱和脂肪酸对高血压也有好处。钠-钙交换器(NCX)活性改变与心律失常、高血压和心力衰竭有关，可能是PUFA的靶点。因此，我们测试了ALA和其他不同的脂肪酸对心脏(NCX 1.1)和血管(NCX 1.3)NCX亚型的影响。方法：在没有和存在25 mU油酸(OA，omega-9)、亚油酸(LA，omega-6)、丙氨酸(Ala，omega-3)或二十碳五烯酸(EPA，omega-3)的情况下，稳定表达NCX亚型的HEK293细胞从+60上升到-100 mV(超过1600ms)。NiCl2(5 MM)被用来抑制和识别NCx电流。通过用Li+取代[Na+](O)后测定[Ca+](I)的方法，观察25 mU M-ALA对成年大鼠心肌细胞和兔主动脉血管平滑肌细胞(VSMC)NCX 1.1和NCX 1.3活性的影响。结果：施加Ni2+对未转染细胞无影响。ALA和EPA(25 MM)使Ni2+敏感的NCX1.1正向电流(-100 mV)和反向电流(+60 mV)分别降低57%和57%，对Ni2+敏感的NCX1.3正向电流和反向电流分别抑制79%和76%。OA和LA(25 MM)均不影响NCX 1.1电流，但均部分抑制正向和反向模式NCX 1.3电流。ALA抑制NCX 1.3的IC50(相当于19 nM)远低于NCX 1.1(相当于120 nM)。在心肌细胞和VSMC中，ALA显著降低Li+诱导的细胞内[Ca~(2+)]升高。结论：NCX 1.3比NCX 1.1对ALA的抑制更为敏感。此外，只有omega-3多不饱和脂肪酸抑制NCX 1.1，但几类脂肪酸抑制NCX 1.3。NCX亚型对脂肪酸的不同敏感性可能对高血压、心力衰竭和心律失常的治疗具有重要意义。(C)2006年欧洲心脏病学会。爱思唯尔出版，版权所有。
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.