Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling.

Abstract

Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Dysregulation of intracellular Ca2+ 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 Ca2+ 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.

• 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
• Journal: Communications biology (Commun Biol) Vol. 3 Issue 1 Pg. 714 (11 26 2020) ISSN: 2399-3642 [Electronic] England
• PMID: 33244105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calmodulin
• Ryanodine Receptor Calcium Release Channel
• ryanodine receptor 2. mouse
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Signaling (genetics, physiology)
• Calmodulin (metabolism)
• Cardiomegaly (metabolism, physiopathology)
• Female
• Heart (physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (cytology, metabolism, pathology)
• Pressure
• Protein Binding
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)