Published Online
on May 9, 2005

A more recent version of this article appeared on May 17, 2005

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Submitted on August 20, 2004
Revised on December 7, 2004
Accepted on December 27, 2004

Dysregulated Osteoprotegerin/RANK Ligand/RANK Axis in Clinical and Experimental Heart Failure

Thor Ueland PhD^*, Arne Yndestad MSc, Erik ie MD, PhD, Geir Florholmen MSc, Bente Halvorsen PhD, Stig S. Frøland MD, PhD, Svein Simonsen MD, PhD, Geir Christensen MD, PhD, Lars Gullestad MD, PhD, and Pål Aukrust MD, PhD

From the Research Institute for Internal Medicine (T.U., A.Y., B.H., S.S.F., P.A.), Section of Endocrinology (T.U.), Institute for Surgical Research (E..), Section of Clinical Immunology and Infectious Diseases (S.S.F., P.A.), Department of Cardiology (S.S.), Rikshospitalet University Hospital, Oslo, Norway; Institute for Experimental Medical Research (G.F., G.C.), Ullevål University Hospital, Oslo, Norway; Department of Medicine (E..), Diakonhjemmet Hospital, Oslo, Norway; and Department of Cardiology (L.G.), Bærum Hospital, Bærum, Norway.

^* To whom correspondence should be addressed. E-mail: thor.ueland{at}medisin.uio.no.

Background--Persistent inflammation appears to play a role in the development of heart failure (HF). Osteoprotegerin (OPG), the receptor activator of nuclear factor-B (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.

Methods and 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.

Key words: heart failure • immunohistochemistry • molecular biology • myocytes • immunology

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