| First Author | Pavlovic D | Year | 2013 |
| Journal | J Mol Cell Cardiol | Volume | 61 |
| Pages | 164-71 | PubMed ID | 23612119 |
| Mgi Jnum | J:279185 | Mgi Id | MGI:6356474 |
| Doi | 10.1016/j.yjmcc.2013.04.013 | Citation | Pavlovic D, et al. (2013) Nitric oxide regulates cardiac intracellular Na(+) and Ca(2)(+) by modulating Na/K ATPase via PKCepsilon and phospholemman-dependent mechanism. J Mol Cell Cardiol 61:164-71 |
| abstractText | In the heart, Na/K-ATPase regulates intracellular Na(+) and Ca(2+) (via NCX), thereby preventing Na(+) and Ca(2+) overload and arrhythmias. Here, we test the hypothesis that nitric oxide (NO) regulates cardiac intracellular Na(+) and Ca(2+) and investigate mechanisms and physiological consequences involved. Effects of both exogenous NO (via NO-donors) and endogenously synthesized NO (via field-stimulation of ventricular myocytes) were assessed in this study. Field stimulation of rat ventricular myocytes significantly increased endogenous NO (18 +/- 2 muM), PKCepsilon activation (82 +/- 12%), phospholemman phosphorylation (at Ser-63 and Ser-68) and Na/K-ATPase activity (measured by DAF-FM dye, western-blotting and biochemical assay, respectively; p<0.05, n=6) and all were abolished by Ca(2+)-chelation (EGTA 10mM) or NOS inhibition l-NAME (1mM). Exogenously added NO (spermine-NONO-ate) stimulated Na/K-ATPase (EC50=3.8 muM; n=6/grp), via decrease in Km, in PLM(WT) but not PLM(KO) or PLM(3SA) myocytes (where phospholemman cannot be phosphorylated) as measured by whole-cell perforated-patch clamp. Field-stimulation with l-NAME or PKC-inhibitor (2 muM Bis) resulted in elevated intracellular Na(+) (22 +/- 1.5 and 24 +/- 2 respectively, vs. 14 +/- 0.6mM in controls) in SBFI-AM-loaded rat myocytes. Arrhythmia incidence was significantly increased in rat hearts paced in the presence of l-NAME (and this was reversed by l-arginine), as well as in PLM(3SA) mouse hearts but not PLM(WT) and PLM(KO). We provide physiological and biochemical evidence for a novel regulatory pathway whereby NO activates Na/K-ATPase via phospholemman phosphorylation and thereby limits Na(+) and Ca(2+) overload and arrhythmias. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". |
