At concentrations found in humans after ingestion of one to two cups of
green tea,
epicatechin-3-gallate (ECG) modulates Na/K-
ATPase conformation and activity. Akin to
ouabain, an archetypal Na/K-
ATPase ligand of the
cardiotonic steroid (CTS) family, ECG also activates
protein kinase C epsilon type (PKCε) translocation and increases the force of contraction of the rat heart. This study evaluated whether, like
ouabain, ECG also modulates Na/K-
ATPase/Src receptor function and triggers pre- and postconditioning against
ischemia/reperfusion (I/R) injury. In vitro, ECG activated the purified Na/K-
ATPase/Src complex. In Langendorff-perfused rat hearts, submicromolar concentrations of ECG administered either before or after
ischemia reduced
infarct size by more than 40%, decreased
lactate dehydrogenase release, and improved the recovery of cardiac function. ECG protection was blocked by PKCε inhibition and attenuated by mitochondrial
KATP channel inhibition. In a unique mammalian cell system with depleted Na/K-
ATPase α1 expression, ECG-induced PKCε activation persisted but protection against I/R was blunted. Taken together, these results reveal a Na/K-
ATPase- and PKCε-dependent mechanism of protection by ECG that is also distinct from the mechanism of action of
ouabain. These ECG properties likely contribute to the positive impact of
green tea consumption on cardiovaascular health and warrant further investigation into the role of cardiac Na/K-
ATPase signaling in the cardioprotective effect of
green tea consumption. SIGNIFICANCE STATEMENT: Consumption of
green tea, the richest dietary source of ECG, is associated with a reduced risk of cardiac mortality.
Antioxidant effects of ECG and other
tea polyphenols are well known, but reported for concentrations well above dietary levels. Therefore, the mechanism underlying the cardioprotective effect of
green tea remains incompletely understood. This study provides experimental evidence that ECG concentrations commonly detected in humans after consumption of a cup of
tea trigger the Na/K-
ATPase/Src receptor in a cell-free system, activate a CTS-like signaling pathway, and provide PKCε-dependent protection against
ischemia/reperfusion injury in rat hearts. Mechanistic studies in mammalian cells with targeted Na/K-
ATPase depletion revealed that although Na/K-
ATPase does not mediate ECG-induced PKCε activation, it is required for ECG-induced protection against
ischemia/reperfusion injury.