ABSTRACT
BACKGROUND: Neuregulin-1ß (NRG-1ß) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 (GGF2) isoform of NRG-1ß improves cardiac function in rodents after myocardial infarction (MI), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF2 on ventricular remodeling, cardiac function, and global transcription in post-MI swine, as well as potential mechanisms for anti-remodeling effects. METHODS AND RESULTS: MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post-MI, survivors (n=13) received GGF2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post-MI, fractional shortening was higher (32.8% versus 25.3%, P=0.019), and left ventricular (LV) end-diastolic dimension lower (4.5 versus 5.3 cm, P=0.003) in GGF2-treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF2-treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG-1ß reduces myoFbs, and suppresses TGFß-induced phospho-SMAD3 as well as αSMA expression. CONCLUSIONS: These results suggest that GGF2/NRG-1ß prevents adverse remodeling after injury in part via anti-fibrotic effects in the heart.
Subject(s)
Heart Failure/drug therapy , Myocardium/pathology , Neuregulin-1/pharmacology , Ventricular Function, Left/drug effects , Ventricular Remodeling/drug effects , Actins/metabolism , Animals , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Drug , Fibrosis , Gene Expression Regulation/drug effects , Heart Failure/genetics , Heart Failure/metabolism , Heart Failure/pathology , Heart Failure/physiopathology , Male , Mice, Inbred C57BL , Myocardial Contraction/drug effects , Myocardium/metabolism , Myofibroblasts/drug effects , Myofibroblasts/metabolism , Myofibroblasts/pathology , Phosphorylation , Rats, Sprague-Dawley , Smad3 Protein/metabolism , Swine , Time Factors , Transcription, Genetic/drug effects , Ventricular Remodeling/geneticsABSTRACT
Through the detection of acute inflammation, edema, and fibrosis, cardiac magnetic resonance imaging provides a complete and safe evaluation of the myocardium in Churg-Strauss disease and is a useful tool for following the disease course.
