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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.

SUBMITTER: Hathaway CK

PROVIDER: S-EPMC4413291 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Hathaway Catherine K CK Grant Ruriko R Hagaman John R JR Hiller Sylvia S Li Feng F Xu Longquan L Chang Albert S AS Madden Victoria J VJ Bagnell C Robert CR Rojas Mauricio M Kim Hyung-Suk HS Wu Bingruo B Zhou Bin B Smithies Oliver O Kakoki Masao M

Proceedings of the National Academy of Sciences of the United States of America 20150406 16

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 ...[more]

PMID: 25848038

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Project description:BackgroundAcidemia, is associated with reduced cardiac function in animals, but no studies showing an effect of acidemia on cardiac function in humans are reported. In the present study, we examined the effect of acidemia on cardiac function assessed with transpulmonary thermodilution technique with integrated pulse contour analysis (Pulse Contour Cardiac Output, PiCCO™) in a large cohort of critically ill patients.MethodsThis was a prospective multicenter observational cross-sectional study of 297 patients from 6 intensive care units in London, England selected from all patients admitted consecutively between May 2018 and March 2019. Measurements of lowest plasma pH and concurrent assessment of cardiac function were obtained.FindingsThere was a significant difference between two pH categories (pH ≤ 7.28 vs. pH > 7.28) for the following variables of cardiac function: SVI (difference in means 32.7; 95% CI: 21 to 45 mL/m2; p < 0.001); GEF (18; 95% CI: 11 to 26%; p < 0.001), dPmax (-331; 95% CI: -510 to -153 mmHg/s; p = 0.001), CFI (0.7; 95% CI: 0.2 to 1.3 1/min; p = 0.01) and CPI (0.09; 95% CI: 0.03 to 0.15 W/m2; p < 0.001). However, there was no significant difference in CI (0.13; 95% CI: -0.20 to 0.47 L/min/m2; p = 0.12) between the pH categories. Also, a significant relationship was found between the quantitative pH and the following variables: SVI (132; 95% CI: 77 to 188 mL/m2; p < 0.001), GEF (74.7; 95% CI: 37.1 to 112.4%; p < 0.001), dPmax (-1587; 95% CI: -2361 to -815 mmHg/s; p < 0.001), CFI (3.5; 95% CI: 0.9 to 6.1 /min; p = 0.009), CPI (0.62; 95% CI: 0.36 to 0.88 W/m2; p < 0.001) and CI (regression coefficient 1.96; 95% CI:0.45 to 3.47 L/min/m2; p = 0.01).InterpretationAcidemia is associated with impaired cardiac function in seriously ill patients hospitalized in the intensive care unit supporting the potential value of early diagnosis and improvement of arterial pH in these patients.FundingThe study was partially supported by unrestricted funds from the UCLA School of Medicine.

Dataset Information

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

Publications

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

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