SOCS1 gene transfer accelerates the transition to heart failure through the inhibition of the gp130/JAK/STAT pathway.

Authors:
Antonio Cittadini
Antonio Cittadini
Federico II University
Napoli | Italy
Maria Gaia Monti
Maria Gaia Monti
University Federico II
Italy
Prof. Guido Iaccarino, MD, PhD
Prof. Guido Iaccarino, MD, PhD
Federico II University of Naples
Full Professor of Applied Medical Science and Technology
Cardiology
Napoli, Campania | Italy
Maria Carmina Castiello
Maria Carmina Castiello
San Raffaele Telethon Institute for Gene Therapy
Italy
Alfonso Baldi
Alfonso Baldi
Second University of Naples
Italy
Eduardo Bossone
Eduardo Bossone
University Hospital
New Brunswick | United States
Salvatore Longobardi
Salvatore Longobardi
University Federico II
Italy
Alberto Maria Marra
Alberto Maria Marra
University Federico II
Italy

Cardiovasc Res 2012 Dec 8;96(3):381-90. Epub 2012 Aug 8.

Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy.

Aims: The suppressors of cytokine signalling (SOCS) are identified inhibitors of cytokine and growth factor signalling that act via the Janus kinase (JAK) signal transducers and activators of transcription (STAT) pathways. Aberrant JAK/STAT signalling promotes progression from hypertrophy to heart failure. Little information is available concerning the role of SOCS in the transition from hypertrophy to heart failure. To this aim, we investigated the effects of SOCS1 overexpression obtained by in vivo adeno-associated gene transfer using an aortopulmonary cross-clamping technique in a chronic pressure-overload cardiac rat model.

Methods And Results: Rats were randomized into four groups: sham-operated (n = 18), aortic banding (AB) (n = 18), AB + viral vector encoding for haemoagglutinin (AB + HA, n = 16), and AB + viral vector encoding for SOCS1 (AB + SOCS1, n = 18). Echocardiographic and haemodynamic measurements were performed 15 weeks after banding. While SOCS3 was upregulated during the hypertrophic phase, SOCS1 transcript levels increased significantly between 15 and 20 weeks. Remodelling was markedly worse in AB + SOCS1, showed larger left ventricular internal dimensions (+16%), higher end-diastolic pressures (+57%) and wall stress (+45%), and reduced fractional shortening (-32%) compared with AB + HA; apoptotic rate was increased three-fold and the gp130 pathway was inhibited. Ex vivo experiments showed that mechanical stretch upregulated SOCS1 expression, which was in turn attenuated by tumour necrosis factor-α (TNF-α) inhibition.

Conclusion: Enhanced SOCS1 myocardial signalling is associated with accelerated transition from hypertrophy to failure in an established model of pressure overload. SOCS1 may represent an attractive target for the prevention of heart failure progression.

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Source
http://dx.doi.org/10.1093/cvr/cvs261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732068PMC

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December 2012
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