© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Na+–Ca2+ exchanger overexpression predisposes to reactive oxygen species-induced injury
aDepartment of Cardiology and Pneumology, Georg-August-University Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany
bInstitute of Physiology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
*Corresponding author. Tel.: +49-551-396380; fax: +49-551-392953. Email address: hkogler{at}med.uni-goettingen.de
Objective: In heart failure (HF), the generation of reactive oxygen species (ROS) is enhanced. It was shown that failing cardiac myocytes are more susceptible to ROS-induced damage, possibly due to increased expression of the sarcolemmal Na–Ca exchanger (NCX). Methods: We investigated the consequences of increased expression levels of NCX in adult rabbit ventricular cardiomyocytes (via adenovirus-mediated gene transfer, Ad-NCX1-GFP) with respect to tolerance towards ROS. After 48-h incubation, cells were monitored for morphological changes on an inverted microscope. ROS were generated via hydrogen peroxide (H2O2) (100 µmol/l) and Fe3+/nitrilotriacetate (Fe3+/NTA, 100/200 µmol/l) for 4 min and cell morphology was followed over 30 min. [Na+]i and [Ca2+]i in native cells were measured using SBFI-AM and Indo1-AM, respectively. Results: In native myocytes, exposure to ROS induced hypercontracture. This was accompanied by a 1.3-fold increase in diastolic Indo1 fluorescence ratio (P<0.05). Overexpression of NCX significantly enhanced development of hypercontracture. After 15 min, the percentage of cells that had undergone hypercontracture (Fhyper) was 85±4% vs. only 44±10% in control cells (P<0.05). Inhibition of NCX-mediated Ca2+ entry with KB-R7943 (5 µmol/l) reduced Fhyper to 33±11% (P<0.05). [Na+]i was increased 2.9-fold 1 min prior to hypercontracture (P<0.05). Conclusions: ROS-induced hypercontracture is due to Ca2+ entry via NCX which could be triggered by a concomitant substantial increase in [Na+]i. Elevated NCX levels predispose to ROS-induced injury, a mechanism likely contributing to myocyte dysfunction and death in heart failure.
KEYWORDS Calcium; Free radicals; Heart failure; Na/Ca-exchanger; N/H-exchanger
Time for primary review 26 days
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