title: Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload.
abstract: OBJECTIVE
  To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca(2+) overload in ventricular myocytes and to explore the underlying mechanisms.
  
  
  METHODS
  Hydrogen peroxide (H2O2, 200 μmol/L)) was used to induce oxidative stress in rabbit ventricular myocytes. Cell shortening and calcium transients were simultaneously recorded to detect arrhythmogenic activity and to measure intracellular Ca(2+) ([Ca(2+)]i). Ca(2+)/calmodulin-dependent protein kinases II (CaMKII) activity was measured using a CaMKII kit or Western blotting analysis. Voltage-activated Na(+) and Ca(2+) currents were examined using whole-cell recording in myocytes.
  
  
  RESULTS
  H2O2 markedly prolonged Ca(2+) transient duration (CaTD), and induced early afterdepolarization (EAD)-like and delayed afterdepolarization (DAD)-like arrhythmogenic activity in myocytes paced at 0.16 Hz or 0.5 Hz. Application of resveratrol (30 or 50 μmol/L) dose-dependently suppressed H2O2-induced EAD-like arrhythmogenic activity and attenuated CaTD prolongation. Co-treatment with resveratrol (50 μmol/L) effectively prevented both EAD-like and DAD-like arrhythmogenic activity induced by H2O2. In addition, resveratrol markedly blunted H2O2-induced diastolic [Ca(2+)]i accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H2O2 significantly enhanced the late Na(+) current (I(Na,L)) and L-type Ca(2+) current (I(Ca,L)) in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H2O2-induced ROS production and CaMKII activation were significantly prevented by resveratrol.
  
  
  CONCLUSIONS
  Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca(2+) overload through inhibition of I(Na,L)/I(Ca,L), reduction of ROS generation, and prevention of CaMKII activation.
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yue-peng
authors.initials: YP
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.forename: Peng-pai
authors.initials: PP
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Quan-fu
authors.initials: QF
authors.lastname: Xu
authors.forename: Zhi-wen
authors.initials: ZW
authors.lastname: Zhou
authors.forename: Kai
authors.initials: K
authors.lastname: Guo
authors.forename: Ren-hua
authors.initials: RH
authors.lastname: Chen
authors.forename: Huang-tian
authors.initials: HT
authors.lastname: Yang
authors.forename: Yi-gang
authors.initials: YG
authors.lastname: Li
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D017382:Reactive Oxygen Species; D013267:Stilbenes; D000077185:Resveratrol; D002118:Calcium
references.citation: Am J Physiol Cell Physiol. 2011 Sep;301(3):C577-86
references.pmid: 21677263
references.citation: Cardiovasc Drugs Ther. 2008 Dec;22(6):479-85
references.pmid: 18853243
references.citation: Am J Respir Crit Care Med. 2012 Oct 1;186(7):648-56
references.pmid: 22822026
references.citation: Eur J Pharmacol. 2010 Dec 15;649(1-3):293-300
references.pmid: 20869962
references.citation: Circ Res. 2009 Jan 2;104(1):79-86
references.pmid: 19038865
references.citation: Circ Res. 2011 Mar 4;108(5):555-65
references.pmid: 21252154
references.citation: Circ Heart Fail. 2009 Nov;2(6):664-75
references.pmid: 19919992
references.citation: Mol Interv. 2002 Nov;2(7):431-46
references.pmid: 14993406
references.citation: J Biol Chem. 2012 Jun 8;287(24):19856-69
references.pmid: 22514276
references.citation: Circ Res. 2000 Sep 1;87(5):392-8
references.pmid: 10969037
references.citation: Antioxid Redox Signal. 2001 Dec;3(6):1041-64
references.pmid: 11813979
references.citation: Circulation. 2013 Feb 5;127(5):575-84
references.pmid: 23271797
references.citation: J Mol Cell Cardiol. 2011 Jan;50(1):128-36
references.pmid: 21059353
references.citation: J Pharmacol Exp Ther. 2006 Jul;318(1):214-22
references.pmid: 16565163
references.citation: Free Radic Biol Med. 2011 Nov 1;51(9):1708-16
references.pmid: 21854842
references.citation: Heart Rhythm. 2011 May;8(5):762-9
references.pmid: 21184845
references.citation: Antioxid Redox Signal. 2013 Mar 20;18(9):1063-77
references.pmid: 22900788
references.citation: J Cardiovasc Pharmacol. 2011 Jul;58(1):40-8
references.pmid: 21753257
references.citation: Biochem Biophys Res Commun. 2006 Feb 24;340(4):1192-9
references.pmid: 16406237
references.citation: Mol Cell Biochem. 1996 Oct-Nov;163-164:125-30
references.pmid: 8974047
references.citation: Cardiovasc Res. 2003 Nov 1;60(2):404-12
references.pmid: 14613870
references.citation: Biochem Biophys Res Commun. 1998 Aug 28;249(3):938-42
references.pmid: 9731240
references.citation: Circ Arrhythm Electrophysiol. 2011 Dec;4(6):947-57
references.pmid: 22009705
references.citation: Circulation. 2011 Apr 26;123(16):1713-20
references.pmid: 21482963
references.citation: Circ Arrhythm Electrophysiol. 2009 Jun;2(3):295-304
references.pmid: 19808480
references.citation: Am J Hypertens. 2010 Feb;23(2):192-6
references.pmid: 19942861
references.citation: Cell. 2008 May 2;133(3):462-74
references.pmid: 18455987
references.citation: Lancet. 1992 Jun 20;339(8808):1523-6
references.pmid: 1351198
references.citation: J Am Coll Cardiol. 2011 Jan 18;57(3):366-75
references.pmid: 21232675
references.citation: Theor Appl Genet. 2005 Nov;111(8):1553-62
references.pmid: 16160820
references.citation: Eur J Pharmacol. 2007 Jan 12;554(2-3):196-204
references.pmid: 17107672
references.citation: Arch Biochem Biophys. 2012 Nov 15;527(2):74-80
references.pmid: 22633977
references.citation: Circulation. 1998 Apr 28;97(16):1536-9
references.pmid: 9593557