Copyright © 2004, European Society of Cardiology
Response of adrenomedullin system to cytokine in cardiac fibroblasts–role of adrenomedullin as an antifibrotic factor
aDepartment of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan
bLaboratory of Molecular and Cellular Biology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan
cResearch Institute, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565, Japan
* Corresponding author. Tel.: +81 282 87 2149; fax: +81 282 86 1596. Email address: nishikim{at}dokkyomed.ac.jp
Objective: The adrenomedullin system acts as an autocrine or paracrine factor (or both) in the development of cardiac hypertrophy and in the regulation of cardiac function. However, several aspects of the local action of adrenomedullin remain unclear. We studied the effects of interleukin 1-beta (IL-1β) on the adrenomedullin system in cardiac fibroblasts and also examined the pathophysiological significance of such effects.
Methods: We cultured rat neonatal cardiac fibroblasts with or without IL-1β and measured (1) two molecular forms of adrenomedullin in culture medium by specific immunoradiometric assay; (2) gene expression of adrenomedullin, calcitonin receptor like receptor (CRLR), receptor activity modifying protein2 (RAMP2), and RAMP3, components of the adrenomedullin receptor, by Northern blot analysis or RT-PCR analysis; (3) intracellular cAMP levels in response to exogenously administered adrenomedullin; and (4) 3H-proline incorporation with and without a specific adrenomedullin antisense oligodeoxynucleotide.
Results: (1) IL-1β time-dependently increased the levels of two molecular forms of adrenomedullin, adrenomedullin-mature and adrenomedullin-glycine (P<0.01). In contrast to known levels in plasma (about 10%), adrenomedullin-mature was a major molecular form in the culture medium of cardiac fibroblasts and myocytes (65–80%). (2) IL-1β significantly increased gene expression of adrenomedullin and its receptor components (adrenomedullin: +46%, CRLR: +460%, RAMP2: +32%, RAMP3: +350%, all P<0.01). (3) Preincubated IL-1β elevated the intracellular cAMP response to exogenous adrenomedullin administered at a concentration of 10–7 M (+26%, P<0.05). (4) Adrenomedullin antisense oligodeoxynucleotide treatment significantly lowered adrenomedullin–mature levels in culture medium (–50%). Adrenomedullin nonsense oligodeoxynucleotide treatment did not change 3H-proline incorporation or mRNA levels of collagen I and III, whereas adrenomedullin antisense oligodeoxynucleotide treatment significantly increased 3H-proline incorporation and mRNA levels of collagen I and III in IL-1β-treated cardiac fibroblasts.
Conclusion: These results provide evidence that the adrenomedullin system acts as an autocrine antifibrotic factor in the regulation of collagen synthesis in cardiac fibroblasts exposed to higher cytokine levels. This may beneficially modulate the pathophysiology of certain cardiac diseases.
KEYWORDS Adrenomedullin; Heart failure; Hypertrophy; Cytokine; Fibrosis; Interleukin 1-beta
Time for primary review 17 days
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