An autocrine or a paracrine role of adrenomedullin in modulating cardiac fibroblast growth

doi:10.1016/S0008-6363(99)00122-4

Cardiovascular Research 1999 43(4):958-967; doi:10.1016/S0008-6363(99)00122-4
© 1999 by European Society of Cardiology

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An autocrine or a paracrine role of adrenomedullin in modulating cardiac fibroblast growth

Toshihiro Tsuruda^a, Johji Kato^a, Kazuo Kitamura^a, Mari Kawamoto^a, Kenji Kuwasako^a, Takuroh Imamura^a, Yasushi Koiwaya^a, Tetsuo Tsuji^b, Kenji Kangawa^c and Tanenao Eto^a^,*

^aFirst Department of Internal Medicine, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
^bShionogi & Co., Ltd., Mishima, Settsu, Osaka 566-0022, Japan
^cDepartment of Biochemistry, National Cardiovascular Center Research Institute, Fujishirodai, Suita, Osaka 565-8565, Japan

^* Corresponding author. Tel.: +81-985-851510 (ext. 2193); fax: +81-985-856596

Objective: The aim of the present study was to determine therole of adrenomedullin (AM) in cardiac fibroblasts. Methods:The production and secretion of AM were examined in culturedneonatal rat cardiac fibroblasts, and the effects of AM on proliferationand protein synthesis of these cells were assessed by [³H]thymidineand [³H]phenylalanine incorporation, respectively. Results:Cultured cardiac fibroblasts secreted AM into the medium time-dependentlyat a rate of 20.3±3.0 fmol/5x10⁴ cells/48 h, mean±S.D.Northern blot analysis showed expression of preproAM mRNA of1.6 kb in these cells. In addition, 10^–6 mol/l of angiotensinII (Ang II) and endothelin-1 (ET-1) significantly increasedthe AM secretion by 55 and 48%, respectively. Synthetic AM significantlyreduced 10^–6 mol/l Ang II- or 10^–7 mol/l ET-1-stimulated[³H]thymidine and [³H]phenylalanine incorporation in a dose-dependentmanner, and these effects were attenuated by a calcitonin gene-relatedpeptide (CGRP) type 1 receptor antagonist, CGRP(8-37). SyntheticAM also had a dose-dependent stimulatory effect on cAMP accumulationin these cells, which was significantly attenuated by CGRP(8-37).A cAMP analogue, 8-bromo-cAMP, mimicked the AM effects, inhibitingthe Ang II-stimulated [³H]thymidine and [³H]phenylalanine incorporation.Blockage of the effect of endogenous AM by anti-AM monoclonalantibody not only significantly reduced the basal level of intracellularcAMP, but also enhanced the [³H]thymidine and [³H]phenylalanineincorporation into the cells. Conclusions: Cultured neonatalrat cardiac fibroblasts produce and secrete AM, and the secretedAM may inhibit proliferation and protein synthesis of thesecells. AM may exert these inhibitory effects partly by elevatingintracellular cAMP. It is suggested that AM has an importantrole in modulating the growth of cardiac fibroblasts in an autocrineor a paracrine manner.

KEYWORDS Adrenomedullin; Fibrosis; Interstitial space; Remodeling; Hormones

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