Elevated levels of activin A in heart failure: potential role in myocardial remodeling.
BACKGROUND
Although modulation of inflammatory processes has been suggested as a new treatment modality in heart failure (HF), our knowledge about abnormalities in the cytokine network during HF is still limited. On the basis of a previous cDNA array study examining peripheral blood mononuclear cells from HF patients, we hypothesized a role for activin A, a member of the transforming growth factor (TGF)-beta superfamily, in the pathogenesis of HF.


RESULTS
This study had 4 main and novel findings. First, serum levels of activin A were significantly elevated in patients with HF (n=86) compared with healthy control subjects (n=20), with increasing levels according to disease severity as assessed by clinical, hemodynamic, and neurohormonal parameters. Second, compared with control subjects, HF patients, as determined by real-time quantitative reverse transcriptase polymer chain reaction, also had markedly increased gene expression of the activin A subunit activin betaA in T cells but not in monocytes. Third, in a rat model of HF, we demonstrated a concerted induction of the gene expression of activin betaA and activin receptors IA, IB, IIA, and IIB after myocardial infarction. Immunohistochemical analysis localized activin A solely to cardiomyocytes. Finally, activin A markedly increased gene expression of mediators involved in infarction healing and myocardial remodeling (ie, atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta1, and monocyte chemoattractant protein-1) in neonatal rat cardiomyocytes.


CONCLUSIONS
Together with our demonstration of activin A-induced gene expression in neonatal cardiomyocytes of mediators related to myocardial remodeling, the expression pattern of activin A during clinical and experimental HF suggests an involvement of this cytokine in the pathogenesis of HF.
Yndestad
Arne
A
Research Institute for Internal Medicine, Rikshospitalet University Hospital, University of Oslo, N-0027 Oslo, Norway. arne.yndestad@klinmed.uio.no
Ueland
Thor
T
Øie
Erik
E
Florholmen
Geir
G
Halvorsen
Bente
B
Attramadal
Håvard
H
Simonsen
Svein
S
Frøland
Stig S
SS
Gullestad
Lars
L
Christensen
Geir
G
Damås
Jan Kristian
JK
Aukrust
Pål
P
D030201:Activin Receptors, Type I / Q000096:biosynthesis / Q000235:genetics; D030301:Activin Receptors, Type II / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D018932:Chemokine CCL2; D005260:Female; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000097:blood* / Q000235:genetics / Q000473:pathology; D006801:Humans; D028322:Inhibin-beta Subunits / Q000097:blood* / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D023421:Models, Animal; D009000:Monocytes / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis / Q000235:genetics; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology*
C111835:CCL2 protein, human; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D011506:Proteins; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C103008:inhibin beta A subunit; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D028322:Inhibin-beta Subunits; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A; C425584:activin receptor type II-B; D020780:Matrix Metalloproteinase 9