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Sacherer, M; Sedej, S; Wakuła, P; Wallner, M; Vos, MA; Kockskämper, J; Stiegler, P; Sereinigg, M; von Lewinski, D; Antoons, G; Pieske, BM; Heinzel, FR; CONTICA investigators.
JTV519 (K201) reduces sarcoplasmic reticulum Ca²⁺ leak and improves diastolic function in vitro in murine and human non-failing myocardium.
Br J Pharmacol. 2012; 167(3):493-504 Doi: 10.1111/j.1476-5381.2012.01995.x [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Heinzel Frank
Sacherer Michael
Co-Autor*innen der Med Uni Graz
Antoons Gudrun
Pieske Burkert Mathias
Sedej Simon
Sereinigg Michael
Stiegler Philipp
von Lewinski Dirk
Wakula-Heinzel Paulina
Wallner Markus

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BACKGROUND AND PURPOSE Ca2+ leak from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR2s) contributes to cardiomyocyte dysfunction. RyR2 Ca2+ leak has been related to RyR2 phosphorylation. In these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca2+ leak. We investigated whether JTV519 stabilizes RyR2s without increasing RyR2 phosphorylation in mice and in non-failing human myocardium and explored underlying mechanisms. EXPERIMENTAL APPROACH SR Ca2+ leak was induced by ouabain in murine cardiomyocytes. [Ca2+]-transients, SR Ca2+ load and RyR2-mediated Ca2+ leak (sparks/waves) were quantified, with or without JTV519 (1 mu mol.L-1). Contribution of Ca2+-/calmodulin-dependent kinase II (CaMKII) was assessed by KN-93 and Western blot (RyR2-Ser2814 phosphorylation). Effects of JTV519 on contractile force were investigated in non-failing human ventricular trabeculae. KEY RESULTS Ouabain increased systolic and diastolic cytosolic [Ca2+]i, SR [Ca2+], and SR Ca2+ leak (Ca2+ spark (SparkF) and Ca2+ wave frequency), independently of CaMKII and RyR-Ser2814 phosphorylation. JTV519 decreased SparkF but also SR Ca2+ load. At matched SR [Ca2+], Ca2+ leak was significantly reduced by JTV519, but it had no effect on fractional Ca2+ release or Ca2+ wave propagation velocity. In human muscle, JTV519 was negatively inotropic at baseline but significantly enhanced ouabain-induced force and reduced its deleterious effects on diastolic function. CONCLUSIONS AND IMPLICATIONS JTV519 was effective in reducing SR Ca2+ leak by specifically regulating RyR2 opening at diastolic [Ca2+]i in the absence of increased RyR2 phosphorylation at Ser2814, extending the potential use of JTV519 to conditions of acute cellular Ca2+ overload.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Calcium - metabolism
Diastole -
Heart Ventricles - drug effects
Humans -
Mice -
Myocardium - metabolism
Myocytes, Cardiac - drug effects
Ouabain - pharmacology
Phosphorylation -
Ryanodine Receptor Calcium Release Channel - metabolism
Sarcoplasmic Reticulum - metabolism
Systole -
Thiazepines - pharmacology

Find related publications in this database (Keywords)
calcium leak
diastolic dysfunction
non-failing human myocardium
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