title: The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury.
abstract: The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 channels were functional since activation with H2O2 resulted in Ca(2+) influx that was dependent on extracellular Ca(2+), was significantly higher in wild-type (WT) myocytes compared with TRPM2 knockout (KO) myocytes, and inhibited by clotrimazole in WT myocytes. At rest, there were no differences in LV mass, heart rate, fractional shortening, and +dP/dt between WT and KO hearts. At 2-3 days after ischemia-reperfusion (I/R), despite similar areas at risk and infarct sizes, KO hearts had lower fractional shortening and +dP/dt compared with WT hearts. Compared with WT I/R myocytes, expression of the Na(+)/Ca(2+) exchanger (NCX1) and NCX1 current were increased, expression of the α1-subunit of Na(+)-K(+)-ATPase and Na(+) pump current were decreased, and action potential duration was prolonged in KO I/R myocytes. Post-I/R, intracellular Ca(2+) concentration transients and contraction amplitudes were equally depressed in WT and KO myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation, levels of ROS were significantly higher in KO compared with WT LV myocytes. Compared with WT I/R hearts, oxygen radical scavenging enzymes (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factor) were lower, whereas NADPH oxidase was higher, in KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/R-induced oxidative stress.
authors: Center of Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Barbara A
authors: BA
authors: Miller
authors: JuFang
authors: J
authors: Wang
authors: Iwona
authors: I
authors: Hirschler-Laszkiewicz
authors: Erhe
authors: E
authors: Gao
authors: Jianliang
authors: J
authors: Song
authors: Xue-Qian
authors: XQ
authors: Zhang
authors: Walter J
authors: WJ
authors: Koch
authors: Muniswamy
authors: M
authors: Madesh
authors: Karthik
authors: K
authors: Mallilankaraman
authors: Tongda
authors: T
authors: Gu
authors: Shu-jen
authors: SJ
authors: Chen
authors: Kerry
authors: K
authors: Keefer
authors: Kathleen
authors: K
authors: Conrad
authors: Arthur M
authors: AM
authors: Feldman
authors: Joseph Y
authors: JY
authors: Cheung
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003022:Clotrimazole; D004452:Echocardiography; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006339:Heart Rate; D006352:Heart Ventricles / Q000473:pathology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D002118:Calcium; D003022:Clotrimazole; D051858:Forkhead Transcription Factors; D006861:Hydrogen Peroxide; D051793:Hypoxia-Inducible Factor 1; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D012964:Sodium; D019831:Sodium-Calcium Exchanger; D000254:Sodium-Potassium-Exchanging ATPase; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D050053:TRPM Cation Channels; D000099156:Superoxide Dismutase 2; C499849:NCX1 protein, mouse; C544443:TRPM2 protein, mouse; C000606291:Sod1 protein, mouse; C497344:Atp1a1 protein, mouse
references: Am J Physiol. 1982 Sep;243(3):C184-90
references: 7114249
references: Circ Res. 2008 Feb 15;102(3):347-55
references: 18048770
references: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7461-6
references: 12032305
references: Naunyn Schmiedebergs Arch Pharmacol. 2004 Oct;370(4):227-37
references: 15549272
references: J Gen Physiol. 2006 May;127(5):525-37
references: 16636202
references: J Biol Chem. 2002 Dec 13;277(50):48303-10
references: 12377790
references: Cell Death Differ. 2006 Oct;13(10):1815-26
references: 16294211
references: Cancer Res. 1998 Apr 1;58(7):1515-20
references: 9537257
references: Am J Physiol Heart Circ Physiol. 2010 Mar;298(3):H807-15
references: 20008271
references: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5860-5
references: 8650183
references: Am J Physiol Heart Circ Physiol. 2012 Feb 1;302(3):H770-81
references: 22081699
references: J Pharmacol Sci. 2006 May;101(1):66-76
references: 16651700
references: Pflugers Arch. 2005 Oct;451(1):212-9
references: 15952035
references: Br J Pharmacol. 2008 Mar;153(6):1324-30
references: 18204483
references: J Biol Chem. 1996 May 24;271(21):12610-6
references: 8647872
references: J Biol Chem. 2006 Feb 3;281(5):2489-96
references: 16316998
references: Biochem Biophys Res Commun. 2003 Aug 1;307(3):713-8
references: 12893282
references: Nat Immunol. 2011 Nov 20;13(1):29-34
references: 22101731
references: Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2199-209
references: 16751288
references: Annu Rev Physiol. 2006;68:619-47
references: 16460286
references: Circ Res. 2002 Nov 29;91(11):1015-22
references: 12456487
references: Am J Physiol. 1992 Mar;262(3 Pt 1):C664-71
references: 1312780
references: Genomics. 1998 Nov 15;54(1):124-31
references: 9806837
references: J Physiol. 2011 Apr 1;589(Pt 7):1791-801
references: 21486840
references: Cell Calcium. 2011 Sep;50(3):279-87
references: 21616534
references: Mol Cell. 2005 Apr 1;18(1):61-9
references: 15808509
references: Am J Physiol. 1995 Dec;269(6 Pt 2):H2147-54
references: 8594926
references: Circ Res. 2010 Dec 10;107(12):1445-53
references: 20966393
references: J Physiol. 2011 Apr 1;589(Pt 7):1515-25
references: 21135052
references: Cardiovasc Res. 1998 Feb;37(2):279-89
references: 9614485
references: Adv Exp Med Biol. 2011;704:531-44
references: 21290315
references: Science. 2001 Aug 17;293(5533):1327-30
references: 11509734
references: Cardiovasc Res. 2013 Feb 1;97(2):271-81
references: 23129587
references: Biochem Biophys Res Commun. 2005 Mar 25;328(4):1232-43
references: 15708008
references: J Appl Physiol (1985). 2001 May;90(5):1720-8
references: 11299261
references: N Engl J Med. 1998 Sep 24;339(13):900-5
references: 9744975
references: Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2181-90
references: 21949114
references: J Biol Chem. 2006 Apr 7;281(14):9076-85
references: 16461353
references: Mol Cell. 2002 Jan;9(1):163-73
references: 11804595
references: Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7239-44
references: 19372375
references: Am J Pathol. 1978 Jul;92(1):187-214
references: 686146
references: Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H590-601
references: 19525383
references: Cell. 2003 Dec 26;115(7):863-77
references: 14697204
references: Annu Rev Biochem. 2007;76:387-417
references: 17579562
references: Am J Physiol Endocrinol Metab. 2012 Apr 1;302(7):E807-16
references: 22275755
references: Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H1932-40
references: 21890689
references: J Biol Chem. 2006 Mar 24;281(12):7784-92
references: 16434394
references: Cell. 2000 May 12;101(4):365-76
references: 10830164
references: Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H859-68
references: 21193587
references: Semin Cell Dev Biol. 2006 Dec;17(6):607-17
references: 17174125
references: Basic Res Cardiol. 2002 Jul;97(4):268-75
references: 12111036
references: Am J Physiol Heart Circ Physiol. 2000 Jul;279(1):H429-36
references: 10899083
references: Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1615-25
references: 18708446