FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure.

Abstract

BACKGROUND:

The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury.

METHODS AND RESULTS:

Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts.

CONCLUSIONS:

During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.

• Authors: Masafumi Yano, Shigeki Kobayashi, Masateru Kohno, Masahiro Doi, Takahiro Tokuhisa, Shinichi Okuda, Masae Suetsugu, Takayuki Hisaoka, Masakazu Obayashi, Tomoko Ohkusa, Michihiro Kohno, Masunori Matsuzaki
• Journal: Circulation (Circulation) Vol. 107 Issue 3 Pg. 477-84 (Jan 28 2003) ISSN: 1524-4539 [Electronic] United States
• PMID: 12551874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ryanodine Receptor Calcium Release Channel
• Thiazepines
• K201 compound
• Cyclic AMP-Dependent Protein Kinases
• Tacrolimus Binding Proteins
• tacrolimus binding protein 1B
• Calcium
• Tacrolimus

Topics

• Animals
• Calcium (metabolism)
• Cyclic AMP-Dependent Protein Kinases (pharmacology)
• Dogs
• Heart Failure (metabolism, physiopathology, prevention & control)
• Hemodynamics
• Ion Transport
• Models, Cardiovascular
• Myocardium (metabolism)
• Phosphorylation
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sarcoplasmic Reticulum (metabolism)
• Tacrolimus (metabolism)
• Tacrolimus Binding Proteins (analysis, metabolism)
• Thiazepines (therapeutic use)
• Ventricular Remodeling