Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade

Catherine K. Hathaway, Ruriko Grant, John R. Hagaman, Sylvia Hiller, Feng Li, Longquan Xu, Albert S. Chang, Victoria J. Madden, C. Robert Bagnell, Mauricio Rojas, Hyung Suk Kim, Bingruo Wu, Bin Zhou, Oliver Smithies, Masao Kakoki

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5141-5146
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number16
DOIs
StatePublished - Apr 21 2015

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Matrix Metalloproteinase 9
Endothelin-1
Superoxides
Plasma Volume
Epithelial Sodium Channel Blockers
Young Adult
Alleles
Dilated Cardiomyopathy
Cardiomyopathies
Cardiac Myocytes
Genetic Recombination
Superoxide Dismutase
Myocardium
Collagen
Blood Pressure
Hypertension
Gene Expression
Genes

Keywords

  • Amiloride
  • Extracellular matrix
  • Reactive oxygen species
  • Sodium retention
  • Tempol

ASJC Scopus subject areas

  • General

Cite this

Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade. / Hathaway, Catherine K.; Grant, Ruriko; Hagaman, John R.; Hiller, Sylvia; Li, Feng; Xu, Longquan; Chang, Albert S.; Madden, Victoria J.; Bagnell, C. Robert; Rojas, Mauricio; Kim, Hyung Suk; Wu, Bingruo; Zhou, Bin; Smithies, Oliver; Kakoki, Masao.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 16, 21.04.2015, p. 5141-5146.

Research output: Contribution to journalArticle

Hathaway, CK, Grant, R, Hagaman, JR, Hiller, S, Li, F, Xu, L, Chang, AS, Madden, VJ, Bagnell, CR, Rojas, M, Kim, HS, Wu, B, Zhou, B, Smithies, O & Kakoki, M 2015, 'Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 16, pp. 5141-5146. https://doi.org/10.1073/pnas.1504557112
Hathaway, Catherine K. ; Grant, Ruriko ; Hagaman, John R. ; Hiller, Sylvia ; Li, Feng ; Xu, Longquan ; Chang, Albert S. ; Madden, Victoria J. ; Bagnell, C. Robert ; Rojas, Mauricio ; Kim, Hyung Suk ; Wu, Bingruo ; Zhou, Bin ; Smithies, Oliver ; Kakoki, Masao. / Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 16. pp. 5141-5146.
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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.",
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AU - Hiller, Sylvia

AU - Li, Feng

AU - Xu, Longquan

AU - Chang, Albert S.

AU - Madden, Victoria J.

AU - Bagnell, C. Robert

AU - Rojas, Mauricio

AU - Kim, Hyung Suk

AU - Wu, Bingruo

AU - Zhou, Bin

AU - Smithies, Oliver

AU - Kakoki, Masao

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