Extracellular superoxide dismutase regulates cardiac function and fibrosis.
Extracellular superoxide dismutase (EC-SOD) is an antioxidant that protects the heart from ischemia and the lung from inflammation and fibrosis. The role of cardiac EC-SOD under normal conditions and injury remains unclear. Cardiac toxicity, a common side effect of doxorubicin, involves oxidative stress. We hypothesize that EC-SOD is critical for normal cardiac function and protects the heart from oxidant-induced fibrosis and loss of function. C57BL/6 and EC-SOD-null mice were treated with doxorubicin, 15 mg/kg (i.p.). After 15 days, echocardiography was used to assess cardiac function. Left ventricle (LV) tissue was used to assess fibrosis and inflammation by staining, Western blot, and hydroxyproline analysis. At baseline, EC-SOD-null mice have LV wall thinning and increases in LV end diastolic dimensions compared to wild-type mice but have normal cardiac function. After doxorubicin, EC-SOD-null mice have decreases in fractional shortening not apparent in WT mice. Lack of EC-SOD also leads to increases in myocardial apoptosis and significantly more LV fibrosis and inflammatory cell infiltration. Administration of the metalloporphyrin AEOL 10150 abrogates the loss of cardiac function, and potentially fibrosis, associated with doxorubicin treatment in both wild-type and EC-SOD KO mice. EC-SOD is critical for normal cardiac morphology and protects the heart from oxidant-induced fibrosis, apoptosis, and loss of function. The antioxidant metalloporphyrin AEOL 10150 effectively protects cardiac function from doxorubicin-induced oxidative stress in vivo. These findings identify targets for the use of antioxidant agents in oxidant-induced cardiac fibrosis.
Kliment
Corrine R
CR
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Suliman
Hagir B
HB
Tobolewski
Jacob M
JM
Reynolds
Crystal M
CM
Day
Brian J
BJ
Zhu
Xiaodong
X
McTiernan
Charles F
CF
McGaffin
Kenneth R
KR
Piantadosi
Claude A
CA
Oury
Tim D
TD
D000818:Animals; D015153:Blotting, Western; D004317:Doxorubicin / Q000494:pharmacology; D004452:Echocardiography; D005260:Female; D005355:Fibrosis / Q000201:enzymology* / Q000235:genetics; D006321:Heart / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D004317:Doxorubicin; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase
Free Radic Biol Med. 2006 Feb 15;40(4):601-7
16458190
Circulation. 2007 Jul 31;116(5):506-14
17638931
Biochem J. 1996 Jan 1;313 ( Pt 1):235-9
8546689
J Biol Chem. 2001 Dec 14;276(50):47266-76
11579094
Circulation. 2005 Aug 16;112(7):1047-53
16087794
Am J Physiol Heart Circ Physiol. 2003 Dec;285(6):H2327-35
12842815
Free Radic Biol Med. 2003 Oct 1;35(7):763-71
14583340
Biochem J. 2005 Jan 15;385(Pt 2):427-32
15362977
Arch Biochem Biophys. 1999 Aug 15;368(2):421-8
10441396
J Biol Chem. 2004 Jul 30;279(31):32243-51
15166218
Biochem Biophys Res Commun. 1985 Jul 31;130(2):739-45
2992484
Cardiovasc Res. 2008 Jan;77(1):54-63
18006469
J Biol Chem. 2004 Apr 2;279(14):13705-10
14736885
Free Radic Biol Med. 2003 Aug 1;35(3):236-56
12885586
Am J Respir Cell Mol Biol. 1997 Oct;17(4):393-403
9376114
Genomics. 1994 Jul 1;22(1):162-71
7959763
J Clin Invest. 1999 Apr;103(7):1055-66
10194479
Hypertension. 2008 Jan;51(1):19-25
17998475
Int J Biochem Cell Biol. 2005 Dec;37(12):2466-71
16087389
Lab Invest. 1994 Jun;70(6):889-98
8015293
Biochim Biophys Acta. 1980 Jun 5;630(1):119-30
6248123
Free Radic Biol Med. 2006 Jun 15;40(12):2223-31
16785036
Circulation. 2004 Jan 6;109(1):59-65
14662715
Biochemistry. 1997 Sep 23;36(38):11293-7
9333325
Am J Pathol. 2008 Mar;172(3):583-91
18245812
Antioxid Redox Signal. 2008 Feb;10(2):261-8
17961072
Am J Respir Cell Mol Biol. 2004 Oct;31(4):432-9
15256385
Free Radic Biol Med. 2002 Oct 1;33(7):988
12361808
J Clin Invest. 2005 May;115(5):1221-31
15841206
Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6264-8
7603981
Cardiovasc Res. 2004 Jun 1;62(3):468-80
15158139
Free Radic Biol Med. 2008 Apr 1;44(7):1305-13
18206658
J Clin Invest. 2000 Aug;106(4):589-97
10953034
Biochem Pharmacol. 2004 Jan 1;67(1):77-85
14667930
Mol Cell Biochem. 2002 May-Jun;234-235(1-2):119-24
12162424
N Engl J Med. 1998 Sep 24;339(13):900-5
9744975
Biol Pharm Bull. 1998 Oct;21(10):1090-3
9821816
Arch Biochem Biophys. 1961 May;93:440-7
13786180
Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H914-20
16840738
J Biol Chem. 2009 Feb 6;284(6):3537-45
19073610
J Appl Physiol (1985). 2004 Nov;97(5):2006-13
15298984
J Biol Chem. 2008 Mar 7;283(10):6058-66
18165226
Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):573-80
17236973
Basic Res Cardiol. 1994 Sep-Oct;89(5):397-410
7535519
Circulation. 1996 Nov 1;94(9 Suppl):II412-7
8901783
Clin Chim Acta. 1992 Nov 30;212(3):89-102
1477980
Hum Mol Genet. 1994 Dec;3(12):2251-4
7881430
Histochem J. 1979 Jul;11(4):447-55
91593
Circ Res. 2008 Nov 21;103(11):1232-40
18845810