title: Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade.
abstract: We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction.
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: Catherine K
authors.initials: CK
authors.lastname: Hathaway
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: Ruriko
authors.initials: R
authors.lastname: Grant
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: John R
authors.initials: JR
authors.lastname: Hagaman
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hiller
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: Longquan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Chang
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Madden
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: C Robert
authors.initials: CR
authors.lastname: Bagnell
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC 27599; and.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461.
authors.forename: Bingruo
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Laboratory Medicine and oliver_smithies@med.unc.edu mkakoki@med.unc.edu.
authors.forename: Oliver
authors.initials: O
authors.lastname: Smithies
authors.affiliation: Department of Pathology and Laboratory Medicine and oliver_smithies@med.unc.edu mkakoki@med.unc.edu.
authors.forename: Masao
authors.initials: M
authors.lastname: Kakoki
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D019332:Endothelin-1; D013481:Superoxides; D003094:Collagen; D013482:Superoxide Dismutase; D020780:Matrix Metalloproteinase 9
keywords: amiloride; extracellular matrix; reactive oxygen species; sodium retention; tempol
references.citation: Mutat Res. 1992 Sep;275(3-6):395-403
references.pmid: 1383780
references.citation: Nature. 1994 Apr 21;368(6473):703-10
references.pmid: 8152482
references.citation: Nat Genet. 1995 Dec;11(4):376-81
references.pmid: 7493016
references.citation: J Cell Biol. 1996 Mar;132(5):849-59
references.pmid: 8603917
references.citation: Clin Sci (Lond). 1996 Jan;90(1):37-46
references.pmid: 8697704
references.citation: Circ Res. 1997 Jan;80(1):114-23
references.pmid: 8978330
references.citation: Circulation. 1997 Nov 4;96(9):3053-62
references.pmid: 9386175
references.citation: Cell. 1998 May 1;93(3):411-22
references.pmid: 9590175
references.citation: Circulation. 2006 Aug 22;114(8):830-7
references.pmid: 16908774
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15038-43
references.pmid: 17015830
references.citation: Am J Physiol Renal Physiol. 2006 Dec;291(6):F1274-80
references.pmid: 16868309
references.citation: Am J Hypertens. 2007 Jan;20(1):32-7
references.pmid: 17198909
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Mar;292(3):R1271-8
references.pmid: 17095651
references.citation: Am J Physiol Renal Physiol. 2008 Oct;295(4):F1063-70
references.pmid: 18667482
references.citation: Genesis. 2010 Jan;48(1):63-72
references.pmid: 20014345
references.citation: J Am Soc Nephrol. 2010 Mar;21(3):527-35
references.pmid: 20167702
references.citation: Biochim Biophys Acta. 2010 Jun;1802(6):509-18
references.pmid: 20176105
references.citation: Nat Med. 2011 Dec;17(12):1610-8
references.pmid: 22081025
references.citation: Am J Physiol Renal Physiol. 2013 Aug 15;305(4):F568-73
references.pmid: 23698114
references.citation: J Clin Invest. 2013 Nov;123(11):4888-99
references.pmid: 24135141
references.citation: Neuron. 2014 Jan 22;81(2):333-48
references.pmid: 24462097
references.citation: Life Sci. 2014 Nov 24;118(2):219-25
references.pmid: 24355292
references.citation: Genesis. 2000 Sep;28(1):15-22
references.pmid: 11020712
references.citation: EMBO J. 2000 Nov 1;19(21):5720-8
references.pmid: 11060023
references.citation: Eur Heart J. 2001 Oct;22(20):1948-53
references.pmid: 11601839
references.citation: Dev Biol. 2002 Apr 15;244(2):305-18
references.pmid: 11944939
references.citation: J Endocrinol. 2002 Oct;175(1):225-32
references.pmid: 12379507
references.citation: Circulation. 2004 Jan 20;109(2):255-61
references.pmid: 14718401
references.citation: J Biol Chem. 2004 Mar 5;279(10):8655-67
references.pmid: 14660616
references.citation: Dev Cell. 2004 Apr;6(4):597-606
references.pmid: 15068798
references.citation: Am J Cardiol. 1991 Oct 15;68(10):1114-5
references.pmid: 1927934