Antibody therapy can enhance AngiotensinII-induced myocardial fibrosis.
BACKGROUND
Myocardial fibrosis is a pathological process that is characterized by disrupted regulation of extracellular matrix proteins resulting in permanent scarring of the heart tissue and eventual diastolic heart failure. Pro-fibrotic molecules including transforming growth factor-β and connective tissue growth factor are expressed early in the AngiotensinII (AngII)-induced and other models of myocardial fibrosis. As such, antibody-based therapies against these and other targets are currently under development.


RESULTS
In the present study, C57Bl/6 mice were subcutaneously implanted with a mini-osmotic pump containing either AngII (2.0 μg/kg/min) or saline control for 3 days in combination with mIgG (1 mg/kg/d) injected through the tail vein. Fibrosis was assessed after picosirius red staining of myocardial cross-sections and was significantly increased after AngII exposure compared to saline control (11.37 ± 1.41%, 4.94 ± 1.15%; P <0.05). Non-specific mIgG treatment (1 mg/kg/d) significantly increased the amount of fibrosis (26.34 ± 3.03%; P <0.01). However, when AngII exposed animals were treated with a Fab fragment of the mIgG or mIgM, this exacerbation of fibrosis was no longer observed (14.49 ± 2.23%; not significantly different from AngII alone).


CONCLUSIONS
These data suggest that myocardial fibrosis was increased by the addition of exogenous non-specific antibodies in an Fc-mediated manner. These findings could have substantial impact on the future experimental design of antibody-based therapeutics.
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Nicole L
NL
Rosin
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Alison J
AJ
Gareau
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Devin
D
Betsch
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Alec
A
Falkenham
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Mryanda J
MJ
Sopel
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada ; Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada ; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Timothy Dg
TD
Lee
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada ; Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada ; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada ; Department of Surgery, New Halifax Infirmary, 1796 Summer St., Room 2269, Halifax, NS B3H 3A7, Canada.
Jean-Francois
JF
Légaré
AngiotensinII; Antibody; Collagen; Inflammation; Myocardial fibrosis