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Cardiovascular Research Advance Access first published online on October 25, 2007
This version [Corrected Proof] published online on November 27, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm047
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Bidirectional regulation of Ca2+ sparks by mitochondria-derived reactive oxygen species in cardiac myocytes

Yuan Yan1, Jie Liu2,*, Chaoliang Wei1, Kaitao Li1, Wenjun Xie1, Yanru Wang1 and Heping Cheng1,*

1 Institute of Molecular Medicine, National Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China
2 Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China

* Corresponding author. Tel/fax: +86 10 6276 5957. E-mail address: chengp{at}pku.edu.cn (H.C.); jieliu{at}fimmu.com (J.L.)

Aims: The cardiac ryanodine receptor (RyR) Ca2+ release channel homotetramer harbours ~21 potentially redox-sensitive cysteine residues on each subunit and may act as a sensor for reactive oxygen species (ROS), linking ROS homeostasis to the regulation of Ca2+ signalling. In cardiac myocytes, arrayed RyRs or Ca2+ release units are packed in the close proximity of mitochondria, the primary source of intracellular ROS production. The present study investigated whether and how mitochondria-derived ROS regulate Ca2+ spark activity in intact cardiac myocytes.

Methods and results: Bidirectional manipulation of mitochondrial ROS production in intact rat cardiac myocytes was achieved by photostimulation and pharmacological means. Simultaneous measurement of intracellular ROS and Ca2+ signals was performed using confocal microscopy in conjunction with the indicators 5-(–6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (for ROS) and rhod-2 (for Ca2+). Photoactivated or antimycin A (AA, 5 µg/mL)-induced mitochondrial ROS production elicited a transient increase in Ca2+ spark activity, followed by gradual spark suppression. Intriguingly, photoactivated mitochondrial ROS oscillations subsequent to the initial peaks mirrored phasic depressions of the spark activity, suggesting a switch of ROS modulation from spark-activating to spark-suppressing. Partial deletion of Ca2+ stores in the sarcoplasmic reticulum contributed in part to the gradual, but not the phasic, spark depression. H2O2 at 200 µM elicited a bidirectional effect on sparks and produced sustained spark activation at 50 µM. Lowering basal mitochondrial ROS production, scavenging baseline ROS, and applying the sulphydryl-reducing agent dithiothreitol diminished the incidence of spontaneous Ca2+ sparks and abolished the Ca2+ spark responses to mitochondrial ROS.

Conclusion: Mitochondrial ROS exert bidirectional regulation of Ca2+ sparks in a dose- and time (history)-dependent manner, and basal ROS constitute a hitherto unappreciated determinant for the production of spontaneous Ca2+ sparks. As such, ROS signalling may play an important role in Ca2+ homeostasis as well as Ca2+ dysregulation in oxidative stress-related diseases.

KEYWORDS Reactive oxygen species (ROS); Ca2+ sparks; Oxidative stress; Cardiac myocytes; Mitochondria

Time for primary review: 18 days


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