Coordinated regulation of murine cardiomyocyte contractility by nanomolar (-)-epigallocatechin-3-gallate, the major green tea catechin.
Green tea polyphenolic catechins exhibit biological activity in a wide variety of cell types. Although 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 Ca(2+) transients, sarcoplasmic reticulum (SR) Ca(2+) content, and ryanodine receptor type 2 (RyR2) channel open probability. Voltage-clamp experiments demonstrate that 10 nM EGCG significantly inhibits the Na(+)-Ca(2+) exchanger. Of importance, other Na(+) and Ca(2+) handling proteins such as Ca(2+)-ATPase, Na(+)-H(+) exchanger, and Na(+)-K(+)-ATPase were not affected by EGCG ≤ 1 μM. Thus, nanomolar EGCG increases contractility in intact myocytes by coordinately modulating SR Ca(2+) loading, RyR2-mediated Ca(2+) release, and Na(+)-Ca(2+) exchange. Inhibition of Na(+)-K(+)-ATPase activity probably 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 the therapeutic and toxicological potential of green tea supplementation is evaluated and may provide a novel therapeutic strategy for improving contractile function in heart failure.
Department of Molecular Biosciences, University of California, Davis, California, USA.
Wei
W
Feng
Hyun Seok
HS
Hwang
Dmytro O
DO
Kryshtal
Tao
T
Yang
Isela T
IT
Padilla
Asheesh K
AK
Tiwary
Birgit
B
Puschner
Isaac N
IN
Pessah
Björn C
BC
Knollmann
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013237:Stereoisomerism; D013662:Tea / Q000737:chemistry*
D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium