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Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure

Galindo, Cristi L. ; Kasasbeh, Ehab ; Murphy, Abigail ; Ryzhov, Sergey ; Lenihan, Sean ; Ahmad, Farhaan A. ; Williams, Philip ; Nunnally, Amy ; Adcock, Jamie ; Song, Yanna ; Harrell, Frank E. ; Tran, Truc‐Linh ; Parry, Tom J. ; Iaci, Jen ; Ganguly, Anindita ; Feoktistov, Igor ; Stephenson, Matthew K. ; Caggiano, Anthony O. ; Sawyer, Douglas B. ; Cleator, John H.

Journal of the American Heart Association, 2014-10, Vol.3 (5), p.e000773-n/a [Periódico revisado por pares]

England: Blackwell Publishing Ltd

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Título:
Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure
Autor: Galindo, Cristi L. ; Kasasbeh, Ehab ; Murphy, Abigail ; Ryzhov, Sergey ; Lenihan, Sean ; Ahmad, Farhaan A. ; Williams, Philip ; Nunnally, Amy ; Adcock, Jamie ; Song, Yanna ; Harrell, Frank E. ; Tran, Truc‐Linh ; Parry, Tom J. ; Iaci, Jen ; Ganguly, Anindita ; Feoktistov, Igor ; Stephenson, Matthew K. ; Caggiano, Anthony O. ; Sawyer, Douglas B. ; Cleator, John H.
Assuntos: Actins - metabolism ; Animals ; Cells, Cultured ; Disease Models, Animal ; Dose-Response Relationship, Drug ; extracellular matrix ; fibroblasts ; Fibrosis ; Gene Expression Regulation - drug effects ; Heart Failure - drug therapy ; Heart Failure - genetics ; Heart Failure - metabolism ; Heart Failure - pathology ; Heart Failure - physiopathology ; Male ; Mice, Inbred C57BL ; Myocardial Contraction - drug effects ; myocardial infarction ; Myocardium - metabolism ; Myocardium - pathology ; Myofibroblasts - drug effects ; Myofibroblasts - metabolism ; Myofibroblasts - pathology ; neuregulin ; Neuregulin-1 - pharmacology ; Original Research ; Phosphorylation ; Rats, Sprague-Dawley ; Smad3 Protein - metabolism ; Swine ; Time Factors ; Transcription, Genetic - drug effects ; Ventricular Function, Left - drug effects ; Ventricular Remodeling - drug effects ; Ventricular Remodeling - genetics
É parte de: Journal of the American Heart Association, 2014-10, Vol.3 (5), p.e000773-n/a
Notas: Dr Galindo and Dr Kasasbeh contributed equally to the manuscript.
An accompanying Table S1 is available at http://jaha.ahajournals.org/content/3/5/e000773/suppl/DC1
Dr Sawyer and Dr Cleator contributed equally to the manuscript.
Descrição: Background Neuregulin‐1β (NRG‐1β) 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‐1β 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‐1β reduces myoFbs, and suppresses TGFβ‐induced phospho‐SMAD3 as well as αSMA expression. Conclusions These results suggest that GGF2/NRG‐1β prevents adverse remodeling after injury in part via anti‐fibrotic effects in the heart.
Editor: England: Blackwell Publishing Ltd
Idioma: Inglês

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Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure

England: Blackwell Publishing Ltd

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