Inhibition of Na⁺‐H⁺ exchange as a mechanism of rapid cardioprotection by resveratrol

Abstract

BACKGROUND AND PURPOSEResveratrol is a polyphenol abundantly found in grape skin and red wine. In the present study, we investigated whether resveratrol exerts protective effects against cardiac ischaemia/reperfusion and also explored its mechanisms. EXPERIMENTAL APPROACHInfarct size and functional recovery in rat isolated perfused hearts subjected to no-flow global ischaemia followed by reperfusion were measured. Cultured neonatal rat cardiomyocytes were exposed to H2O2 (100 mmol·L -1 ) to induce cell injury. Intracellular ion concentrations were measured using specific dyes. Western blotting was used to quantify protein expression levels. KEY RESULTSIn rat isolated perfused hearts, treatment with resveratrol (20 and 100 mmol·L -1 ) 15 min before ischaemia considerably improved left ventricular functional recovery and infarct size. In cultured neonatal rat cardiomyocytes, resveratrol significantly attenuated the increase in reactive oxygen species (ROS) and loss of mitochondrial inner membrane potential. Resveratrol also suppressed the increase in intracellular concentrations of Na + ([Na + ]i) and Ca 2+ ([Ca 2+ ]i) after H2O2 application; however, it did not suppress the ouabain-induced [Ca 2+ ]i increase. By measuring changes in intracellular pH recovery after acidification, we also confirmed that acid-induced activation of the Na + -H + exchanger (NHE) was prevented by pretreatment with resveratrol. Furthermore, resveratrol inhibited the H2O2-induced translocation of PKC-a from the cytosol to the cell membrane; this translocation is believed to activate NHE. CONCLUSION AND IMPLICATIONSResveratrol exerts cardioprotection by reducing ROS and preserving mitochondrial function. The PKC-a-dependent inhibition of NHE and subsequent attenuation of [Ca 2+ ]i overload may be a cardioprotective mechanism. AbbreviationsDYm, mitochondrial inner membrane potential; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; LV, left ventricular; LVDP, left ventricular developed pressure; mitoKATP, mitochondrial ATP-sensitive K + channels; mPTP, mitochondrial permeability transition pore; NCX, Na + -Ca 2+ exchanger; NHE, Na + -H + exchanger; PI, propidium iodide; PMA, phorbol 12-myristate 13-acetate; ROS, reactive oxygen species; TMRE, tetramethylrhodamine ethyl ester

Hyponatraemia aggravates cardiac susceptibility to ischaemia/reperfusion injury

“…In fact, previous studies revealed that NCX inhibitors such as KB‐R7943 and SEA0400 exerted cardioprotective effects against ischaemia/reperfusion injury by attenuating [Ca 2+ ] i overload . Consistently, we previously demonstrated that resveratrol exerted cardioprotection by suppressing NCX‐mediated increase in [Ca 2+ ] i level induced by H 2 O 2 . As mentioned above, hyponatraemia may activate the reverse mode of the NCX and increases [Ca 2+ ] i concentration, which leads to phosphorylation of CaMKII and increase in ROS levels .…”

Resveratrol: Inhibitory Effects on Metastatic Cell Behaviors and Voltage-Gated Na+Channel Activity in Rat Prostate Cancer In Vitro

“…A recently identified target of resveratrol is the Na C /H C exchanger type 1 (NHE1) (46). Interestingly, NHE1 activity was shown earlier to be increased by VGSC activity in breast cancer cells and the resulting pericellular acidification contributed to extracellular proteolysis and invasiveness (47).…”

Resveratrol and polydatin as modulators of Ca2+mobilization in the cardiovascular system

“…Ca 2+ overload can be induced by the depression of SR Ca 2+ recycling and enhancement of diastolic SR Ca 2+ leak. Furthermore, it can be induced by intracellular acidosis (pH i ) through the activation of the sarcolemmal Na + –H + exchanger (NHE) to extrude H + driven by the transmembrane Na + gradient in cardiomyocytes . Increases in the intracellular concentration of Na + ([Na + ] i ) induced by increased Na + –H + exchange facilitate Ca 2+ influx through the NCX working in reverse mode.…”

“…Furthermore, intracellular Ca 2+ overload leads to mitochondrial Ca 2+ overload, which induces mitochondrial permeability transition pore opening and consequent apoptosis . A series of studies has indicated that Res prevents intracellular Ca 2+ overload by inhibiting the activation of NHE . Recently, the newly developed Res analog HS‐1793 (4‐(6‐hydroxy‐2‐naphthyl)‐1,3‐benzenediol, 10 μM) was shown to prevent mitochondrial Ca 2+ overload and attenuate mitochondrial damage .…”