PT  - JOURNAL ARTICLE
AU  - Yiyao Qi
AU  - Changjun Yang
AU  - Zhen Jiang
AU  - Yin Wang
AU  - Feng Zhu
AU  - Tao Li
AU  - Xiaochun Wan
AU  - Yunhui Xu
AU  - Zijian Xie
AU  - Daxiang Li
AU  - Sandrine V. Pierre
TI  - Epicatechin-3-Gallate Signaling and Protection against Cardiac Ischemia/Reperfusion Injury
AID  - 10.1124/jpet.119.260117
DP  - 2019 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 663--674
VI  - 371
IP  - 3
4099  - http://jpet.aspetjournals.org/content/371/3/663.short
4100  - http://jpet.aspetjournals.org/content/371/3/663.full
SO  - J Pharmacol Exp Ther2019 Dec 01; 371
AB  - 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.