Copyright © 2005, European Society of Cardiology
Etanercept or intravenous immunoglobulin attenuates expression of genes involved in post-myocardial infarction remodeling
aDepartment of Medicine, Division of Cardiology, University of California, San Diego, Medical Center, 200 W Arbor Drive, San Diego, California, CA 92103-8411, USA
bResearch Institute for Internal Medicine, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
cSection of Clinical Immunology and Infectious Diseases, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
dDepartment of Cardiology, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
* Corresponding author. Tel.: +1 619 543 7751; fax: +1 619 543 7870. Email address: bgreenberg{at}ucsd.edu
Objective: Persistently elevated levels of inflammatory cytokines such as tumor necrosis factor (TNF)
after acute myocardial infarction (MI) may contribute to maladaptive ventricular remodeling. The aim of the present study was to examine the effects of immunomodulatory therapy with recombinant soluble TNF receptor (TNFR:Fc) or intravenous immunoglobulin (IVIg) on left and right ventricular post-MI remodeling in rats.
Methods and results: Adult male Sprague–Dawley rats were subjected to MI by left coronary artery ligation and randomized to treatment with vehicle, TNFR:Fc, or IVIg and sacrificed after 7 days. The main findings were that: (i) TNFR:Fc- and IVIg-treated rats developed less right ventricular (RV) hypertrophy compared to vehicle-treated controls. (ii) LV and arterial pressures in post-MI rats were not affected by the TNFR:Fc or IVIg treatment. (iii) As determined by real-time RT-PCR, both treatments reduced the expression of the hypertrophy-related genes, atrial natriuretic peptide and the ratio of β/-myosin heavy chains, and genes related to extracellular matrix remodeling (i.e., collagens I and III, matrix metalloproteinase [MMP]-2 and its tissue inhibitor TIMP-1) in the non-ischemic segment of LV and, in particular, in the RV. (iv) Treatment with IVIg, but not TNFR:Fc, reduced MMP-2 zymographic activity in the RV and the expression of genes for TNF and monocyte chemoattractant protein-1.
Conclusion: Therapy targeted directly against TNF (i.e., TNFR:Fc) and a more general immunomodulatory approach (i.e., IVIg) in the acute phase of MI attenuates the cardiac remodeling process and expression of genes that are involved. These findings raise the possibility that initiation of immunomodulatory therapy post-MI could be beneficial in preventing the later development of heart failure.
KEYWORDS Infarction; Cytokines; Remodeling
1 Both authors contributed equally.
* This work was funded in part by NIH grant RO1 HL63909 (BG) and grants from the Norwegian Research Council and Prof. Hall's fund for heart research.
Time for primary review 25 days
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