Relationship between natriuretic peptides and inflammation: proteomic evidence obtained during acute cellular cardiac allograft rejection in humans.
BACKGROUND
Cardiac natriuretic peptides (NPs) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are polypeptide hormones secreted by the heart. Previously, we found that BNP, but not ANF, plasma levels may increase during an acute cellular cardiac allograft rejection episode. In vitro, the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced a selective increase of BNP gene expression and secretion. Other pro-inflammatory cytokines had no such effects.


METHODS
We identified cytokines associated with the selective upregulation of BNP during cardiac allograft rejection using a proteomics approach to measure 120 cytokines and related substances in the plasma of 16 transplant patients before, during and after an acute rejection episode. The values obtained were correlated with BNP plasma levels. Cytokines identified as being significantly related to BNP plasma levels were tested in neonatal rat ventricular cardiocytes in culture for their ability to selectively promote BNP secretion. The signaling pathway related to this phenomenon was pharmacologically characterized.


RESULTS
Regulated-on-activation, normal T-expressed and secreted (RANTES), neutrophil-activating protein-2 (NAP-2) and insulin growth factor binding protein-1 (IGFBP-1) had significant correlations with BNP plasma levels during Grade 3A (Grade 2 revised [2R]) or above rejection as diagnosed by endomyocardial biopsy score according to the International Society for Heart and Lung Transplantation (ISHLT) grading system. In rat neonatal ventricular cardiocyte cultures, IGFBP-1 and RANTES were capable of promoting BNP, but not ANF secretion, as observed in rejecting patients. The BNP-promoting secretion activity of the identified cytokines was abolished by SB203580, a specific p38 MAP kinase inhibitor.


CONCLUSIONS
This work shows that cytokines other than pro-inflammatory cytokines correlate with BNP plasma levels observed during acute cardiac allograft rejection, and that the substances identified have in common p38 signaling. This finding provides a unifying mechanistic explanation regarding the relationship between inflammation and cardiac hormone production in acute cardiac allograft rejection.
Meirovich
Yael F
YF
Cardiovascular Endocrinology Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Veinot
John P
JP
de Bold
Mercedes L Kuroski
ML
Haddad
Haissam
H
Davies
Ross A
RA
Masters
Roy G
RG
Hendry
Paul J
PJ
de Bold
Adolfo J
AJ
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000097:blood; D001706:Biopsy; D006328:Cardiac Catheterization; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000097:blood* / Q000473:pathology; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D011379:Prognosis; D011863:Radioimmunoassay; D051381:Rats; D012720:Severity of Illness Index; D014184:Transplantation, Homologous
D016207:Cytokines; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor