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Cardiovascular Research 2001 49(4):695-696; doi:10.1016/S0008-6363(01)00190-0
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

Continuing insights into the heart as an endocrine organ: adrenomedullin and cardiac fibroblasts

Michihisa Jougasaki* and John C Burnett, Jr.

Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, MN 55905, USA

* Corresponding author. Tel.: +1-507-284-4838; fax: +1-507-266-4710 jougasaki{at}mayo.edu

Received 27 December 2000; accepted 28 December 2000

See article by Tomoda et al. [15] (pages 721–730) in this issue.

In 1993, Kitamura et al. [1] discovered a novel hypotensive peptide in human pheochromocytoma by means of monitoring the ability of extracted fractions to increase platelet cyclic adenosine 3',5'-monophosphate (cAMP), which they named adrenomedullin. Human adrenomedullin consists of 52 amino acids and has an intramolecular disulfide bond and C-terminal amide structure, which shows 27% homology with calcitonin gene related peptide (CGRP), suggesting that adrenomedullin belongs to the CGRP superfamily. Adrenomedullin immunoreactivity and its gene expression are widely distributed in cardiovascular, pulmonary, renal, gastrointestinal, cerebral and endocrine tissues. Studies have demonstrated that adrenomedullin elicits a hypotensive effect through at least two mechanisms, a direct action on vascular smooth muscle cells, to increase intracellular cAMP, and an action on endothelial cells, to stimulate nitric oxide release, both of which lead to vascular relaxation [2]. When adrenomedullin is injected intravenously, it increases flow rates predominantly in organs in which the adrenomedullin gene is highly expressed, suggesting that adrenomedullin acts as a local autocrine and/or paracrine vasoactive hormone [3]. Adrenomedullin is also a circulating hormone and its plasma concentration is increased in various cardiorenal diseases, such as hypertension, chronic renal failure and congestive heart failure [4–8].

The regulation of adrenomedullin synthesis and secretion has not been fully elucidated. Adrenomedullin is synthesized and secreted from cultured vascular endothelial cells and smooth muscle cells [9,10]. The important secretagogues for adrenomedullin are cytokines, such as interleukin-1{alpha}, interleukin-1β, tumor necrosis factor-{alpha}, tumor necrosis factor-β [11], and also endothelin via endothelin-B receptor activation [12]. Indeed, adrenomedullin is considered to be associated with endotoxin shock and inflammation, which are both characterized by cytokine and endothelin activation.

A focus upon adrenomedullin and the heart has emerged as a consequence of the increase in plasma adrenomedullin concentrations in human congestive heart failure [5–8]. Importantly, it has been reported that, in the human and canine heart, adrenomedullin immunoreactivity is present and increased in the failing ventricular myocardium [5,13], suggesting that ventricular adrenomedullin expression may be augmented in congestive heart failure. In patients with congestive heart failure from whom plasma samples were obtained from the aorta and the anterior interventricular vein, there was a significant step-up in plasma adrenomedullin concentrations between the aorta and the anterior interventricular vein [6]. As the anterior interventricular vein drains blood from the ventricle, these observations suggest that the failing ventricle secretes adrenomedullin in human congestive heart failure to contribute to the increase in plasma adrenomedullin. Indeed, Romppanen et al. [14] have reported that cardiac overload stimulates ventricular adrenomedullin gene expression in conscious normotensive rats.

In the current issue of Cardiovascular Research, Tomoda et al. [15] present convincing data indicating that cardiac fibroblasts are a major production site for adrenomedullin and are the target cells of biological actions of adrenomedullin in the heart. The authors separated myocytes and non-myocytes (mainly fibroblasts) to a high degree of purity and investigated the regulation of adrenomedullin secretion from these cells. They also examined adrenomedullin effects on production and secretion of interleukin-6, nitric oxide and endothelin-1 from these cells. It has been reported that adrenomedullin is synthesized and secreted from cultured neonatal rat cardiac fibroblasts [16,17] and that adrenomedullin inhibits proliferation and protein synthesis of these cells in an autocrine and/or paracrine fashion [17,18]. We now know that the secretion rate of adrenomedullin from cardiac fibroblasts is higher than that from cardiomyocytes, and that cytokines stimulate adrenomedullin secretion from cardiac fibroblasts, and not from cardiomyocyes. In addition, adrenomedullin stimulates interleukin-6 and nitric oxide production from cardiac fibroblasts in the presence of interleukin-1β. Furthermore, cardiac fibroblasts secrete endothelin-1 much more than cardiomyocytes, while adrenomedullin inhibits endothelin-1 secretion from cardiac fibroblasts. The authors have concluded that adrenomedullin in the heart is mainly produced in cardiac fibroblasts and that adrenomedullin exerts its myocardial effects through this cell type [15].

Another important finding of the current study [15] is that cardiac fibroblasts express receptor-activity-modifying protein 1 (RAMP 1), indicating that cardiac fibroblasts possess receptors with greater affinity to CGRP. Indeed, adrenomedullin-induced production of cAMP, interleukin-6 and nitric oxide is inhibited by the CGRP antagonists in these cells. It has been known that some tissues have ‘adrenomedullin-specific’ receptors that have a high affinity for adrenomedullin but a low affinity for CGRP, and that others have ‘CGRP-specific’ receptors with a high affinity for CGRP but with a low affinity for adrenomedullin [19]. McLatchie et al. [20] have reported that the calcitonin-receptor-like receptor (CRLR), with seven transmembrane domains, and RAMP, with a single transmembrane domain, generate adrenomedullin/CGRP receptors. Adrenomedullin and CGRP share the core receptor CRLR, and RAMP 1, 2 and 3 are the key proteins to determine ligand activity. RAMP 1 converts CRLR to ‘CGRP-specific’ receptor, and RAMPs 2 and 3 convert it to ‘adrenomedullin-specific’ receptor. RAMPs play a role in transporting CRLR to the plasma membrane. The current study [15] supports the concept that tissue-specific RAMPs determine adrenomedullin/CGRP receptors.

During the last two decades, our view of the heart as a pump has evolved to a recognition that the heart is also an endocrine organ. Tomoda et al. [15] have taken us yet another step forward and clearly established that the cardiac fibroblasts, like cardiomyocytes, synthesize and secrete a local peptide hormone that may modulate myocardial structure and function.


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 References
 

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