PT  - JOURNAL ARTICLE
AU  - Wei Feng
AU  - Hyun Seok Hwang
AU  - Dmytro O Kryshtal
AU  - Tao Yang
AU  - Isela T Padilla
AU  - Asheesh K Tiwary
AU  - Birgit Puschner
AU  - Isaac N. Pessah
AU  - Bjorn C. Knollmann
TI  - Coordinated Regulation of Murine Cardiomyocyte Contractility by Nanomolar (-)-epigallocatechin-3-gallate, the Major Green Tea Catechin
AID  - 10.1124/mol.112.079707
DP  - 2012 Jan 01
TA  - Molecular Pharmacology
PG  - mol.112.079707
4099  - http://molpharm.aspetjournals.org/content/early/2012/08/23/mol.112.079707.short
4100  - http://molpharm.aspetjournals.org/content/early/2012/08/23/mol.112.079707.full
AB  - Green tea polyphenolic catechins exhibit biological activity in a wide variety of cell types. While reports in the lay and scientific literature suggest therapeutic potential for improving cardiovascular health, the underlying molecular mechanisms of action remain unclear. Previous studies have implicated a wide range of molecular targets in cardiac muscle for the major green tea catechin, (-)-epigallocatechin-3-gallate (EGCG), but effects were observed only at micromolar concentrations of unclear clinical relevance. Here we report that nanomolar concentrations of EGCG significantly enhance contractility of intact murine myocytes by increasing electrically-evoked Ca2+, transients, sarcoplasmic reticulum (SR) Ca2+ content and ryanodine receptor type 2 (RyR2) channel open probability. Voltage-clamp experiments demonstrate that 10 nM EGCG significantly inhibits the Na+Ca2+ exchanger. Importantly, other Na+ and Ca2+ handling proteins such as Ca2+-ATPase (SERCA2) and Na+-K+ ATPase were not affected by EGCG < 1 μM. Thus, nanomolar EGCG increases contractility in intact myocytes by coordinately modulating SR Ca2+ loading, RyR2-mediated Ca2+ release and Na+ Ca2+ exchange. Inhibition of Na+-K+ ATPase activity likely contributes to the positive inotropic effects observed at EGCG concentrations > 1 μM. These newly recognized actions of nanomolar and micromolar EGCG should be considered when evaluating the therapeutic and toxicological potential of green tea supplementation and may provide a novel therapeutic strategy for improving contractile function in heart failure.