Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure.

Abstract

BACKGROUND:

Calmodulin (CaM) is a key modulator of the channel gating function of the ryanodine receptor (RyR).

OBJECTIVE:

The purpose of this study was to investigate the pathogenic role of RyR-bound CaM in diastolic Ca2+ leakage from the sarcoplasmic reticulum and arrhythmogenesis in pressure-overloaded heart failure.

METHODS:

Pressure overload was induced in 12-week-old mice by transverse aortic constriction (TAC) using a 27-gauge needle.

RESULTS:

TAC operation for 8 weeks produced a significant increase in left ventricular end-diastolic diameter and frequent occurrence of lethal arrhythmias after infusion of epinephrine and caffeine in TAC mice. The amount of RyR-bound CaM decreased significantly in TAC mice compared with sham mice. The apparent affinity of CaM binding to RyR decreased in pressure-overloaded cells compared with sham cells and untreated cells. High-affinity calmodulin (HA-CaM; ie, CaM whose binding affinity to RyR was significantly increased) restored a normal level of CaM-RyR binding properties in pressure-overloaded cells. HA-CaM corrected abnormally increased Ca2+ spark frequency in the pressure-overloaded cells to the level seen in the sham cells. The frequency of spontaneous Ca2+ transients in TAC cells during and after 1-5 Hz of field stimulation was 44%, whereas it was significantly attenuated by HA-CaM but not with CaM.

CONCLUSION:

Several disorders in the RyR channel function characteristic of pressure-overloaded cells (increased spontaneous Ca2+ leakage, delayed afterdepolarization, triggered activity, Ca2+ spark frequency, spontaneous Ca2+ transients) are caused by deteriorated CaM binding to RyR2. These disorders could be rectified by restoring normal CaM binding to RyR2.

• Authors: Takayoshi Kato, Takeshi Yamamoto, Yoshihide Nakamura, Takuma Nanno, Go Fukui, Yoko Sufu, Yoriomi Hamada, Takako Maeda, Shigehiko Nishimura, Hironori Ishiguchi, Wakako Murakami, Masakazu Fukuda, Xiaojuan Xu, Akihiro Hino, Makoto Ono, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Noritaka Koseki, Hiroyuki Kyushiki, Masafumi Yano
• Journal: Heart rhythm (Heart Rhythm) Vol. 14 Issue 1 Pg. 120-127 (01 2017) ISSN: 1556-3871 [Electronic] United States
• PMID: 27771553 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• Calcium Channels
• Calmodulin
• Ryanodine Receptor Calcium Release Channel

Topics

• Animals
• Body Surface Potential Mapping (methods)
• Calcium Channels (metabolism)
• Calcium Signaling
• Calmodulin (metabolism)
• Cells, Cultured
• Disease Models, Animal
• Heart Failure (diagnostic imaging, mortality, therapy)
• Mice
• Mice, Inbred Strains
• Myocytes, Cardiac (metabolism)
• Random Allocation
• Reference Values
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sarcoplasmic Reticulum (metabolism)
• Sensitivity and Specificity
• Tachycardia, Ventricular (diagnosis, mortality, therapy)