Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure.
BACKGROUND
Persistent inflammation appears to play a role in the development of heart failure (HF). Osteoprotegerin (OPG), the receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) are newly discovered members of the tumor necrosis factor superfamily that are critical regulators in bone metabolism but appear also to be involved in immune responses. We hypothesized that the OPG/RANK/RANKL axis could be involved in the pathogenesis of heart failure (HF), and this hypothesis was investigated in both experimental and clinical studies.


RESULTS
Our main and novel findings were as follows: (1) In a rat model of postinfarction HF, we found persistently increased gene expression of OPG, RANK, and RANKL in the ischemic part of the left ventricle (LV) and, for OPG, in the nonischemic part that involved both noncardiomyocyte and in particular cardiomyocyte tissue. (2) Enhanced myocardial protein levels of OPG, RANK, and RANKL, in particular, were also seen in human HF, and using immunohistochemistry, we localized these mediators to cardiomyocytes within the LV in both experimental and clinical HF. (3) In human HF, we also found increased systemic expression of RANKL (T cells and serum) and OPG (serum), with increasing levels according to functional, hemodynamic, and neurohormonal disease severity. (4) RANKL increased total matrix metalloproteinase activity in human fibroblasts, which indicates a matrix-degrading net effect and suggests a potential mechanism by which enhanced RANKL expression in HF may contribute to LV dysfunction.


CONCLUSIONS
These findings suggest a potential role for known mediators of bone homeostasis in the pathogenesis of HF and possibly represents new targets for therapeutic intervention in this disorder.
Ueland
Thor
T
Research Institute for Internal Medicine, Medical Department, Rikshospitalet University Hospital, Oslo, Norway. thor.ueland@medisin.uio.no
Yndestad
Arne
A
Øie
Erik
E
Florholmen
Geir
G
Halvorsen
Bente
B
Frøland
Stig S
SS
Simonsen
Svein
S
Christensen
Geir
G
Gullestad
Lars
L
Aukrust
Pål
P
D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis* / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000032:analysis* / Q000097:blood; D006333:Heart Failure / Q000209:etiology* / Q000473:pathology; D006352:Heart Ventricles / Q000737:chemistry; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000097:blood; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000473:pathology; D053244:Osteoprotegerin; D053245:RANK Ligand; D051381:Rats; D017208:Rats, Wistar; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis* / Q000097:blood; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis* / Q000097:blood; D018487:Ventricular Dysfunction, Left / Q000209:etiology
D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C506032:Tnfrsf11b protein, rat