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Adrenomedullin is increased in alveolar macrophages and released from the lungs into the circulation in severe heart failure

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Abstract

Adrenomedullin (AM) is a potent vasorelaxing peptide with natriuretic, diuretic, and growth inhibitory properties. Plasma concentrations and myocardial AM expression are increased in heart failure (HF). Since AM and AM binding sites are abundantly expressed in the lungs, we investigated to what extent pulmonary AM and AM receptor subtypes [CRLR/RAMP2 (AM1) and CRLR/RAMP3 (AM2)] are changed in HF and whether the lungs contribute to the increased plasma concentrations of AM reported in HF. Pulmonary AM mRNA and protein expression were increased by 2.8- and 2.6-fold, respectively, whereas mRNA expression of RAMP2 and CRLR was decreased in rats with HF 7 days after induction of MI compared to sham-operated rats (P < 0.05). Pulmonary AM receptor density was substantially decreased in HF rats compared to sham (3.7 ± 0.6 vs. 29.9 ± 1.1 fmol/mg membrane protein; P < 0.05). Immunoreactivities against AM and the AM receptor components CRLR, RAMP2, and RAMP3 in the pulmonary tissue were seen in vascular smooth muscle cells, vascular endothelial cells, and in alveolar macrophages. AM mRNA expression in alveolar macrophages obtained from HF rats by bronchoalveolar lavage was 2.9-fold higher than in sham-operated rats (P < 0.05). An even more substantial increase of AM mRNA expression was found in alveolar macrophages from patients with HF (10-fold, P < 0.05), and this increase displayed a negative correlation to left ventricular systolic function (P < 0.05). Furthermore, a net release of AM from the lungs into the circulation was only found in HF patients with the most severe left ventricular systolic dysfunction. Thus, our data demonstrate increased expression and decreased receptor binding of AM in the lungs in severe HF. Furthermore, our data indicate that alveolar macrophages are an important source of pulmonary AM in both experimental and clinical HF. Finally, a net release of AM from the lungs into the circulation was only found in patients with severe systolic dysfunction.

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Authors and Affiliations

  1. Department of Cardiology, Rikshospitalet University Hospital, University of Oslo, 0027, Oslo, Norway

    Erik Øie, Christen P. Dahl, Thor Edvardsen, Arne K. Andreassen & Lars Gullestad

  2. Institute for Surgical Research, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway

    Erik Øie, Mohammed Shakil Ahmed, Else Marie Valbjørn Hagelin, Thomas von Lueder, Leif Erik Vinge & Håvard Attramadal

  3. Research Institute for Internal medicine, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway

    Thor Ueland, Christen P. Dahl, Pål Aukrust & Arne Yndestad

  4. Centre for Occupational and Environmental Medicine, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway

    Liv Ingunn Bjoner Sikkeland

  5. Department of Respiratory Medicine, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway

    Liv Ingunn Bjoner Sikkeland

  6. Section of Clinical Immunology and Infectious Diseases, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway

    Pål Aukrust

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  1. Erik Øie
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Correspondence to Erik Øie.

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Øie, E., Ahmed, M.S., Ueland, T. et al. Adrenomedullin is increased in alveolar macrophages and released from the lungs into the circulation in severe heart failure. Basic Res Cardiol 105, 89–98 (2010). https://doi.org/10.1007/s00395-009-0070-y

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  • DOI: https://doi.org/10.1007/s00395-009-0070-y

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