Skip to Main content Skip to Navigation
Theses

Développement d'une nouvelle approche thérapeutique basée sur IGF-1 pour la cardiomyopathie dilatée dans un modèle de hamster déficient en delta-sarcoglycane

Abstract : Cardiac disorders, among which dilated cardiomyopathy (DCM) is the most common form, are more and more frequently diagnosed in patients affected by muscular dystrophies and largely determine their vital prognosis. In this context, treatments of DCM are those of heart failure that act on the cardiac functional environment but not directly on cardiac muscle.
The goal of this thesis was to evaluate the effects of an innovative treatment of DCM in muscular dystrophies, using the hamster strain CHF147. The approach proposed here is to induce a compensatory phenomenon of cardiac dilatation, and thus to improve vital prognosis, using the Insulin-like Growth Factor-1 (IGF-1) properties.
Young CHF147 hamsters were treated during a short period and systemically with IGF-1 recombinant protein (rhIGF-1) at low dose. The macroscopic, histological and functional effects of the treatment were evaluated after 35 days and signalling pathways implicated in the induction of the observed effects were studied. A survival study was realized in order to assess long-term effects of the treatment. Evaluation of the short-term effects of rhIGF-1 administration on CHF147 hamster's DCM show that dilatation of cardiac cavities and myocardial fibrosis are slowed down, and multiple functional parameters, such as cardiac output, stroke volume, end diastolic pressure and in particular myocardial contractility are preserved. The observed effects are partly due to modifications of proteins implicated in calcium cycle. At long term, survival of treated CHF147 hamsters is significantly improved of about 20% and is associated with a partial preservation of the cardiac function.
However, an increase of IGF-1 serum level could raise the risk for deleterious secondary effects. In order to limit systemic effects of IGF-1 and to target its administration to the heart, we have injected locally the pCMV-IGF1 plasmid coding for IGF-1 in the myocardium of CHF147 hamsters. The effects of the treatment were evaluated after 35 days and showed comparable results as those obtained using rhIGF-1.
In conclusion, this work has shown that a treatment based on IGF-1 allows slowing down the evolution of the CHF147 hamsters' DCM, by preserving the cardiac structure and function, and significantly improves their survival. Thus IGF-1 seems to be a promising candidate to set up a gene therapy approach in heart failure due to DCM in the context of muscular dystrophies.
Complete list of metadatas

Cited literature [121 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-00186657
Contributor : Armelle Serose <>
Submitted on : Saturday, November 10, 2007 - 11:26:55 PM
Last modification on : Wednesday, December 9, 2020 - 3:13:51 PM
Long-term archiving on: : Monday, April 12, 2010 - 1:50:31 AM

Identifiers

  • HAL Id : tel-00186657, version 1

Collections

Citation

Armelle Serose. Développement d'une nouvelle approche thérapeutique basée sur IGF-1 pour la cardiomyopathie dilatée dans un modèle de hamster déficient en delta-sarcoglycane. Biochimie [q-bio.BM]. Université Paris-Diderot - Paris VII, 2007. Français. ⟨tel-00186657⟩

Share

Metrics

Record views

618

Files downloads

1127