Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 16, Pages 5141-5146Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1504557112
Keywords
amiloride; extracellular matrix; reactive oxygen species; sodium retention; tempol
Categories
Funding
- NIH [HL49277, HL70523, HL71266, DK34987]
- Career Development Award from the Juvenile Diabetes Research Foundation [2006-102]
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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, similar to 20%; L/+, similar to 65%; +/+ (wild type), 100%; and H/+, similar to 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 (similar to 35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction.
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