Na(+)-Ca(2+) exchanger overexpression predisposes to reactive oxygen species-induced injury.

Abstract

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 (H(2)O(2)) (100 micromol/l) and Fe(3+)/nitrilotriacetate (Fe(3+)/NTA, 100/200 micromol/l) for 4 min and cell morphology was followed over 30 min. [Na(+)](i) and [Ca(2+)](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 (F(hyper)) was 85+/-4% vs. only 44+/-10% in control cells (P<0.05). Inhibition of NCX-mediated Ca(2+) entry with KB-R7943 (5 micromol/l) reduced F(hyper) 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 Ca(2+) 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.

• Authors: Stefan Wagner, Tim Seidler, Eckard Picht, Lars S Maier, Victor Kazanski, Nils Teucher, Wolfgang Schillinger, Burkert Pieske, Gerrit Isenberg, Gerd Hasenfuss, Harald Kögler
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 60 Issue 2 Pg. 404-12 (Nov 01 2003) ISSN: 0008-6363 [Print] England
• PMID: 14613870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Guanidines
• Sodium-Calcium Exchanger
• Sulfones
• sodium-calcium exchanger 1
• cariporide
• Sodium
• Hydrogen Peroxide
• Calcium

Topics

• Adenoviridae (genetics)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Calcium (metabolism)
• Cells, Cultured
• Female
• Genetic Vectors (administration & dosage)
• Guanidines (pharmacology)
• Heart Failure (metabolism, pathology)
• Hydrogen Peroxide (adverse effects)
• Intracellular Fluid (metabolism)
• Myocytes, Cardiac (metabolism, pathology)
• Rabbits
• Sarcolemma (metabolism)
• Sodium (metabolism)
• Sodium-Calcium Exchanger (antagonists & inhibitors, genetics, metabolism)
• Sulfones (pharmacology)
• Transduction, Genetic (methods)