+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure



A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure



American Journal of Physiology. Heart and Circulatory Physiology 284(3): H1035-H1042



Defective interaction between FKBP12.6 and ryanodine receptors (RyR) is a possible cause of cardiac dysfunction in heart failure (HF). Here, we assess whether the new cardioprotective agent JTV519 can correct it in tachycardia-induced HF. HF was induced in dogs by 4-wk rapid ventricular pacing, and sarcoplasmic reticulum (SR) was isolated from left ventricular muscles. In failing SR, JTV519 increased the rate of Ca(2+) release and [(3)H]ryanodine binding. RyR were then labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetamide. In failing SR, the polylysine induced a rapid change in methylcoumarin acetamide fluorescence, presumably because the channel opening preceding the Ca(2+) release was smaller than in normal SR (consistent with a decreased rate of Ca(2+) release in failing SR), and JTV519 increased it. In conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca(2+) release rate) in HF.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 045079181

Download citation: RISBibTeXText

PMID: 12433661

DOI: 10.1152/ajpheart.00722.2002


Related references

A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure. American Journal of Physiology 284(3): 035-H1042, 2003

A novel cardioprotective agent, JTV519 improves cardiac function by restoring defective channel gating of ryanodine receptor in heart failure. Circulation 104(17 Supplement): II 131, October 23, 2001

PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure. Journal of Cell Biology 160(6): 919-928, 2003

JTV519 restores normal cardiac ryanodine receptor Ca2+ channel function in failing hearts. Circulation 108(17 Supplement): IV-74-IV-75, October 28, 2003

MET-88, a new cardioprotective agent, improves experimentally induced heart failure in the dogs. Japanese Journal of Pharmacology 67(SUPPL 1): 56P, 1995

Insights into the gating mechanism of the ryanodine-modified human cardiac Ca2+-release channel (ryanodine receptor 2). Molecular Pharmacology 86(3): 318-329, 2014

Defective regulation of inter-domain interaction within ryanodine receptor as a cause of heart failure. Circulation 108(17 Supplement): IV-237-IV-238, October 28, 2003

Stabilizing ryanodine receptor gating quiets arrhythmogenic events in human heart failure and atrial fibrillation. Heart Rhythm, 2016

The ryanodine-channel associated protein FKBP126 but not ryanodine-channel-2 expression is increased in human heart failure. Circulation 102(18 Supplement): II 595, October 31, 2000

Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure. Circulation. Arrhythmia and Electrophysiology 6(3): 546-554, 2013

Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure. Circulation 111(25): 3400-3410, 2005

Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure. Circulation 112(23): 3633-3643, 2005

Defective ryanodine receptor interdomain interactions may contribute to intracellular Ca2+ leak: a novel therapeutic target in heart failure. Circulation 111(25): 3342-3346, 2005

Low dose of propranolol prevents the development of heart failure by restoring the defective interaction of FKBP126 with cardiac ryanodine receptor. Journal of the American College of Cardiology 39(5 Supplement A): 165A, March 6, 2002

beta-adrenergic receptor blockers restore cardiac calcium release channel (ryanodine receptor) structure and function in heart failure. Circulation 104(23): 2843-2848, 2001