title: Oxidative stress stimulates autophagic flux during ischemia/reperfusion.
abstract: Autophagy is a bulk degradation process in which cytosolic proteins and organelles are degraded through lysosomes. To evaluate autophagic flux in cardiac myocytes, we generated adenovirus and cardiac-specific transgenic mice harboring tandem fluorescent mRFP-GFP-LC3. Starvation significantly increased the number of mRFP-GFP-LC3 dots representing both autophagosomes and autolysosomes per cell, suggesting that autophagic flux is increased in cardiac myocytes. H(2)O(2) significantly increased autophagic flux, which was attenuated in the presence of N-2-mercaptopropionyl glycine (MPG), an antioxidant, suggesting that oxidative stress stimulates autophagy in cardiac myocytes. Myocardial ischemia/reperfusion (I/R) increased both autophagosomes and autolysosomes, thereby increasing autophagic flux. Treatment with MPG attenuated I/R-induced increases in oxidative stress, autophagic flux, and Beclin-1 expression, accompanied by a decrease in the size of myocardial infarction (MI)/area at risk (AAR), suggesting that oxidative stress plays an important role in mediating autophagy and myocardial injury during I/R. MI/AAR after I/R was significantly reduced in beclin1(+/-) mice, whereas beclin1(+/-) mice treated with MPG exhibited no additional reduction in the size of MI/AAR after I/R. These results suggest that oxidative stress plays an important role in mediating autophagy during I/R, and that activation of autophagy through oxidative stress mediates myocardial injury in response to I/R in the mouse heart.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, UMDNJ, New Jersey Medical School, New Jersey, USA.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Hariharan
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy; D000071186:Beclin-1; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D013217:Starvation; D008625:Tiopronin / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D006861:Hydrogen Peroxide; D008625:Tiopronin
references.citation: Circ Res. 2010 Apr 16;106(7):1253-64
references.pmid: 20185797
references.citation: Antioxid Redox Signal. 2009 Aug;11(8):1975-88
references.pmid: 19327038
references.citation: Circ Res. 2007 Mar 30;100(6):914-22
references.pmid: 17332429
references.citation: Cell. 2008 Jan 11;132(1):27-42
references.pmid: 18191218
references.citation: Circulation. 1994 Apr;89(4):1792-801
references.pmid: 8149545
references.citation: Autophagy. 2008 May;4(4):409-15
references.pmid: 18227645
references.citation: Circ Res. 2009 Jan 30;104(2):150-8
references.pmid: 19179668
references.citation: Genes Dev. 2007 Nov 15;21(22):2861-73
references.pmid: 18006683
references.citation: Cell. 2010 Feb 5;140(3):313-26
references.pmid: 20144757
references.citation: Autophagy. 2010 May;6(4):462-72
references.pmid: 20364102
references.citation: Biochem J. 2003 Apr 15;371(Pt 2):429-36
references.pmid: 12513695
references.citation: Oncogene. 2008 Dec;27 Suppl 1:S137-48
references.pmid: 19641499
references.citation: EMBO J. 2001 Nov 1;20(21):5971-81
references.pmid: 11689437
references.citation: Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2750-5
references.pmid: 15653760
references.citation: Antioxid Redox Signal. 2007 Sep;9(9):1373-81
references.pmid: 17627477
references.citation: Circulation. 1986 May;73(5):1077-86
references.pmid: 3698230
references.citation: Med Sci Monit. 2009 Oct;15(10):RA209-219
references.pmid: 19789524
references.citation: Antioxid Redox Signal. 2006 Jan-Feb;8(1-2):152-62
references.pmid: 16487049
references.citation: Autophagy. 2008 May;4(4):416-21
references.pmid: 18253087
references.citation: Autophagy. 2008 Feb;4(2):151-75
references.pmid: 18188003
references.citation: Biochem Soc Trans. 2006 Apr;34(Pt 2):232-7
references.pmid: 16545083
references.citation: J Cardiovasc Pharmacol. 1986 Sep-Oct;8(5):978-88
references.pmid: 2429100
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13807-12
references.pmid: 16174725
references.citation: Cell Death Differ. 2007 Jan;14(1):146-57
references.pmid: 16645637
references.citation: J Biol Chem. 2007 Aug 17;282(33):24131-45
references.pmid: 17580304
references.citation: Cell Death Differ. 2009 Jan;16(1):31-8
references.pmid: 19008922
references.citation: Autophagy. 2007 Sep-Oct;3(5):452-60
references.pmid: 17534139
references.citation: Thromb Haemost. 2009 Apr;101(4):635-42
references.pmid: 19350105
references.citation: J Cell Biol. 2005 Nov 21;171(4):603-14
references.pmid: 16286508
references.citation: Mol Biol Cell. 2004 Mar;15(3):1101-11
references.pmid: 14699058
references.citation: EMBO J. 2007 Apr 4;26(7):1749-60
references.pmid: 17347651
references.citation: Autophagy. 2009 Jul;5(5):709-12
references.pmid: 19398895
references.citation: Circ J. 2010 Jan;74(1):203-6
references.pmid: 19966504