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

  • Erik ØieEmail author
  • Mohammed Shakil Ahmed
  • Thor Ueland
  • Liv Ingunn Bjoner Sikkeland
  • Christen P. Dahl
  • Else Marie Valbjørn Hagelin
  • Thomas von Lueder
  • Thor Edvardsen
  • Arne K. Andreassen
  • Lars Gullestad
  • Pål Aukrust
  • Arne Yndestad
  • Leif Erik Vinge
  • Håvard Attramadal
Original Contribution

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.

Keywords

Adrenomedullin Alveolar macrophages Heart failure Myocardial infarction RAMP 

Notes

Conflict of interest statement

None.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Erik Øie
    • 1
    • 2
    Email author
  • Mohammed Shakil Ahmed
    • 2
  • Thor Ueland
    • 3
  • Liv Ingunn Bjoner Sikkeland
    • 4
    • 5
  • Christen P. Dahl
    • 1
    • 3
  • Else Marie Valbjørn Hagelin
    • 2
  • Thomas von Lueder
    • 2
  • Thor Edvardsen
    • 1
  • Arne K. Andreassen
    • 1
  • Lars Gullestad
    • 1
  • Pål Aukrust
    • 3
    • 6
  • Arne Yndestad
    • 3
  • Leif Erik Vinge
    • 2
  • Håvard Attramadal
    • 2
  1. 1.Department of CardiologyRikshospitalet University Hospital, University of OsloOsloNorway
  2. 2.Institute for Surgical ResearchRikshospitalet University Hospital, University of OsloOsloNorway
  3. 3.Research Institute for Internal medicineRikshospitalet University Hospital, University of OsloOsloNorway
  4. 4.Centre for Occupational and Environmental MedicineRikshospitalet University Hospital, University of OsloOsloNorway
  5. 5.Department of Respiratory MedicineRikshospitalet University Hospital, University of OsloOsloNorway
  6. 6.Section of Clinical Immunology and Infectious DiseasesRikshospitalet University Hospital, University of OsloOsloNorway

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