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Urotensin-II-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators

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Abstract

Urotensin-II (U-II), the most potent mammalian vasoconstrictor identified, and its receptor, UT, exhibits increased expression in cardiac tissue and plasma in congestive heart failure (CHF) patients. Cardiomyocyte hypertrophy is primarily responsible for increased myocardial mass associated with cardiac injury. Neurohumoral factors such as angiotensin-II, endothelin-1, catecholamines, and inflammatory cytokines are thought to mediate this response. U-II shares similar biological activities with other hypertrophic Gq-coupled receptor ligands such as angiotensin-II and endothelin-1, but a role for U-II in cardiomyocyte hypertrophy has not been characterized. The hypothesis of the current study was that U-II, acting through its Gq-coupled receptor UT plays a hypertrophic role in cardiac hypertrophic remodeling. We report that adenoviral upregulation of the UT receptor “unmasked” U-II-induced hypertrophy in H9c2 cardiomyocytes, with a threshold response of 202±8 binding sites/cell. U-II was equally as efficacious as phenylephrine in inducing hypertrophy, measured by a reporter assay (EC50 0.7±0.2 nM) and [3H]-leucine incorporation (EC50 150±40 nM). A competitive peptidic UT receptor antagonist, BIM-23127, inhibited U-II-induced hypertrophy (K B 34±6 nM). U-II did not affect cell proliferation or apoptosis, indicating that U-II is more hypertrophic than apoptotic or hyperplastic in cardiomyocytes. U-II (10 nM) stimulated interleukin-6 release in UT-expressing cardiomyocytes (4.6-fold at 6 h). Finally, in a rat heart failure model, cardiac ventricular mRNA expression of U-II, UT receptor, interleukin-6, and interleukin-1-β is increased time-dependently following myocardial injury. These results indicate that U-II might play a role in cardiac remodeling associated with CHF by stimulation of cardiomyocyte hypertrophy via UT, and through upregulation of inflammatory cytokines. As such, UT antagonism may represent a novel therapeutic target for the clinical management of heart failure.

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Acknowledgements

Parts of this study were presented at the American Heart Association Scientific Sessions conference, 2002, in Chicago, Illinois, and at the American Heart Association Scientific Sessions conference, 2003, in Orlando, Florida.

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Authors and Affiliations

  1. Department of Vascular Biology and Thrombosis, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, UW2510, King of Prussia, PA, 19406, USA

    Douglas G. Johns, Zhaohui Ao, Diane Naselsky, Nambi Aiyar & Stephen A. Douglas

  2. RheoGene, Inc., Norristown, PA, USA

    Christopher L. Herold

  3. Department of Investigative Support and Cardiac Biology, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, UW2510, King of Prussia, 19406, PA, USA

    Kristeen Maniscalco

  4. Department of Bioinformatics, GlaxoSmithKline, 709 Swedeland Road, UW2510, King of Prussia, 19406, PA, USA

    Lea Sarov-Blat

  5. Department of Quantitative Expression and Genomic Histology, GlaxoSmithKline, 709 Swedeland Road, UW2510, King of Prussia, 19406, PA, USA

    Klaudia Steplewski

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  1. Douglas G. Johns
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  9. Stephen A. Douglas
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Correspondence to Douglas G. Johns.

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Johns, D.G., Ao, Z., Naselsky, D. et al. Urotensin-II-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators. Naunyn-Schmiedeberg's Arch Pharmacol 370, 238–250 (2004). https://doi.org/10.1007/s00210-004-0980-z

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