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The role of angiotensin II, endothelin-1 and transforming growth factor-β as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy

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Abstract

Cardiac hypertrophy is a compensatory response of myocardial tissue upon increased mechanical load. Of the mechanical factors, stretch is rapidly followed by hypertrophic responses. We tried to elucidate the role of angiotensin II (AII), endothelin-1 (ET-1) and transforming growth factor-β (TGF-β) as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy. We collected conditioned medium (CM) from stretched cardiomyocytes and from other stretched cardiac cells, such as cardiac fibroblasts, endothelial cells and vascular smooth muscle cells (VSMCs). These CMs were administered to stationary cardiomyocytes with or without an AII type 1 (AT1) receptor antagonist (losartan), an ET-1 type A (ETA) receptor antagonist (BQ610), or anti-TGF-β antibodies. By measuring the mRNA levels of the proto-oncogene c-fos and the hypertrophy marker gene atrial natriuretic peptide (ANP), the molecular phenotype of the CM-treated stationary cardiomyocytes was characterized.

Our results showed that c-fos and ANP expression in stationary cardiomyocytes was increased by AII release from cardiomyocytes that had been stretched for 60 min. Stretched cardiomyocytes, cardiac fibroblasts and endothelial cells released ET-1 which led to increased c-fos and ANP expression in stationary cardiomyocytes. ET-1 released by stretched VSMCs, and TGF-β released by stretched cardiac fibroblasts and endothelial cells, appeared to be paracrine mediators of ANP expression in stationary cardiomyocytes.

These results indicate that AII, ET-1 and TGF-β (released by cardiac and vascular cell types) act as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy. Therefore, it is likely that in stretched myocardium the cardiomyocytes, cardiac fibroblasts, endothelial cells and VSMCs take part in intercellular interactions contributing to cardiomyocyte hypertrophy.

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Authors and Affiliations

  1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

    Annemieke J.E.T. van Wamel, Cindy Ruwhof, Lizette E.J.M. van der Valk-Kokshoorn & Arnoud van der Laarse

  2. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands

    Peter I. Schriern

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  1. Annemieke J.E.T. van Wamel
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van Wamel, A.J., Ruwhof, C., van der Valk-Kokshoorn, L.E. et al. The role of angiotensin II, endothelin-1 and transforming growth factor-β as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy. Mol Cell Biochem 218, 113–124 (2001). https://doi.org/10.1023/A:1007279700705

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