title: SOCS1 gene transfer accelerates the transition to heart failure through the inhibition of the gp130/JAK/STAT pathway.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy. antonio.cittadini@unina.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Cittadini
authors.forename: Maria Gaia
authors.initials: MG
authors.lastname: Monti
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: Maria Carmina
authors.initials: MC
authors.lastname: Castiello
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bossone
authors.forename: Salvatore
authors.initials: S
authors.lastname: Longobardi
authors.forename: Alberto Maria
authors.initials: AM
authors.lastname: Marra
authors.forename: Valentina
authors.initials: V
authors.lastname: Petrillo
authors.forename: Lavinia
authors.initials: L
authors.lastname: Saldamarco
authors.forename: Matthew John
authors.initials: MJ
authors.lastname: During
authors.forename: Luigi
authors.initials: L
authors.lastname: Saccà
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014463:Ultrasonography; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: D042702:Angiopoietin-2; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C491589:Socs1 protein, rat; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D050822:Cytokine Receptor gp130; C507906:Jak1 protein, rat; D053613:Janus Kinase 1