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Cardiovascular Research 2002 53(2):470-480; doi:10.1016/S0008-6363(01)00464-3
© 2002 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

Regulation of sarcolemmal Na+/H+ exchange by hydrogen peroxide in adult rat ventricular myocytes

Andrew K Snabaitis, David J Hearse and Metin Avkiran*

Centre for Cardiovascular Biology and Medicine, King's College London, The Rayne Institute, St. Thomas’ Hospital, London SE1 7EH, UK

metin.avkiran{at}kcl.ac.uk

* Corresponding author. Tel.: +44-20-7928-9292, ext. 3375; fax: +44-20-7928-0658

Objective: To characterise the effects of exogenous H2O2 on sarcolemmal Na+/H+ exchanger (NHE) activity and determine the roles of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase C (PKC) in observed effects. Methods: Sarcolemmal H+ efflux rate (JH) was determined by microepifluorescence at a pHi of 6.70 in adult rat ventricular myocytes, after two consecutive acid pulses in HCO3–-free medium; before the second pulse, cells (n=7–10/group) were exposed to H2O2 or vehicle and the change in JH ({Delta}JH) was used to quantify the change in NHE activity. ERK and p38 MAPK activities were determined by immunoblotting with phosphospecific antibodies. Results: Relative to control, {Delta}JH was increased by a 10-min exposure to 100, but not 1 or 10 µM H2O2 (1000 µM was not tolerated); 3 or 6 min exposure to 100 µM H2O2 was without effect. ERK and p38 MAPK activities were both increased by 100 µM H2O2 (peak at 6 min); the ERK kinase inhibitor PD98059 (10 µM), but not the p38 MAPK inhibitor SB203580 (1 µM), inhibited the H2O2-induced increase in {Delta}JH. H2O2-induced ERK activation was inhibited not only by PD98059 (10 µM), but also by the non-selective tyrosine kinase inhibitor genistein (3–100 µM), the EGF receptor kinase inhibitor AG1478 (3–300 nM) and the Src family kinase inhibitor PP2 (0.1–10 µM). The PKC inhibitors GF109203X (0.3–10 µM) and chelerythrine (1–30 µM) were without effect on ERK activation, although the former abolished the H2O2-induced increase in {Delta}JH. Conclusions: Our data demonstrate that, in adult rat ventricular myocytes, (i) hydrogen peroxide stimulates sarcolemmal NHE activity, (ii) this response requires activation of ERK and PKC, but not p38 MAPK, (iii) ERK activation occurs through tyrosine kinase-mediated, but PKC-independent, mechanisms

KEYWORDS Free radicals; Myocytes; Na/H-exchanger; Signal transduction; Protein kinases


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