Enhancing Calmodulin Binding to Cardiac Ryanodine Receptor Completely Inhibits Pressure-overload Induced Hypertrophic Signaling

Overview

Journal Commun Biol

Specialty Biology

Date 2020 Nov 27

PMID 33244105

Citations 11

Authors

Michiaki Kohno

Shigeki Kobayashi

Takeshi Yamamoto

Ryosuke Yoshitomi

Toshiro Kajii

Shohei Fujii

Yoshihide Nakamura

Takayoshi Kato

Hitoshi Uchinoumi

Tetsuro Oda

Shinichi Okuda

Kenji Watanabe

Yoichi Mizukami

Masafumi Yano

Affiliations

Soon will be listed here.

Abstract

Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Dysregulation of intracellular Ca is involved in the pathogenesis of cardiac hypertrophy. However, the precise mechanism underlying cardiac hypertrophy remains elusive. Here, we investigate whether pressure-overload induced hypertrophy can be induced by destabilization of cardiac ryanodine receptor (RyR2) through calmodulin (CaM) dissociation and subsequent Ca leakage, and whether it can be genetically rescued by enhancing the binding affinity of CaM to RyR2. In the very initial phase of pressure-overload induced cardiac hypertrophy, when cardiac contractile function is preserved, reactive oxygen species (ROS)-mediated RyR2 destabilization already occurs in association with relaxation dysfunction. Further, stabilizing RyR2 by enhancing the binding affinity of CaM to RyR2 completely inhibits hypertrophic signaling and improves survival. Our study uncovers a critical missing link between RyR2 destabilization and cardiac hypertrophy.

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