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Regulation of norepinephrine-induced proliferation in cardiac fibroblasts by interleukin-6 and p42/p44 mitogen activated protein kinase

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Abstract

Norepinephrine (NE) is involved in many cardiovascular diseases such as congestive heart failure. We have recently reported that NE had a comitogenic effect in isolated cardiac fibroblasts, and that it activated p42/p44 mitogen activated protein kinase (MAPK). This study was designed to characterize a possible mechanism involved in the proliferative effect of NE. Isolated rat cardiac fibroblasts were exposed to NE (10μM) for up to 8 h, and interleukin-6 (IL-6) expression was measured by Ribonuclease Protection Assay and Western blotting. The activity of p42/p44MAPK was analyzed by Western blotting. Cell number was assessed by use of a Coulter Counter. IL-6/GAPDH mRNA was increased by NE in a time-dependent manner reaching 23 fold stimulation after 1 h compared to untreated samples. Immunoreactivity to IL-6 was not found in controls. After 16h of exposure to NE, IL-6 protein was detected. It further increased up to 48 h. The effect of NE on IL-6 mRNA was abolished by the β-adrenoceptor blockers propranolol, metoprolol (β1) and ICI 118.551 (β2), but not by the α-adrenoceptor blockers prazosin (α1) and yohimbine (α2). The MAPK-inhibitor PD98059 suppressed the NE-induced MAPK activation in a concentration-dependent fashion after 5 min, attenuated the NE-induced IL-6 expression after 2 h, and suppressed the proliferative effect of NE from 53 to 18% after 48 h. Recombinant IL-6 caused an increase in proliferation by 31% after 48 h. Simultaneous application of the IL-6 antibody reduced the NE-induced proliferation to 34%, and completely prevented the IL-6 induced effect. These results suggest that NE induces proliferation of rat cardiac fibroblasts in part by increasing the expression of IL-6 through regulation of MAPK.

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Authors and Affiliations

  1. Carl-Ludwig-Institute of Physiology, University of Leipzig, Germany

    Monika Leicht, Wilfried Briest & Heinz-Gerd Zimmer

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  1. Monika Leicht
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  2. Wilfried Briest
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  3. Heinz-Gerd Zimmer
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Leicht, M., Briest, W. & Zimmer, HG. Regulation of norepinephrine-induced proliferation in cardiac fibroblasts by interleukin-6 and p42/p44 mitogen activated protein kinase. Mol Cell Biochem 243, 65–72 (2003). https://doi.org/10.1023/A:1021655023870

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