title: Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 during cardiac remodelling in rats.
abstract: OBJECTIVE
  Accumulating evidence supports the concept that proinflammatory cytokines play an essential role in the failing heart. We examined the concomitant tumour necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 expression in myocytes in vitro as well as in vivo in cardiac remodelling.
  
  
  METHODS
  We assessed TWEAK and its receptor Fn14 expression in response to angiotensin (Ang) II, myocardial infarction (MI) as well as to local adenovirus-mediated p38 gene transfer in vivo. The effect of various hypertrophic factors and mechanical stretch was studied in neonatal rat ventricular myocyte cell culture.
  
  
  RESULTS
  Ang II increased Fn14 levels from 6 h to 2 weeks, the greatest increase in mRNA levels being observed at 6 h (6.3-fold, P < 0.001) and protein levels at 12 h (4.9-fold, P < 0.01). TWEAK mRNA and protein levels remained almost unchanged during Ang II infusion. Likewise, a rapid and sustained elevation of Fn14 mRNA and protein levels in the left ventricle was observed after experimental MI. Moreover, local p38 gene transfer increased Fn14 mRNA and protein but not TWEAK levels. Fn14 immunoreactive cells were mainly proliferating non-myocytes in the inflammation area while TWEAK immunoreactivity localized to cardiomyocytes and endothelial cells of the coronary arteries. Hypertrophic agonists and lipopolysaccharide increased Fn14 but not TWEAK gene expression in neonatal rat myocytes, while mechanical stretch upregulated Fn14 and downregulated TWEAK gene expression.
  
  
  CONCLUSIONS
  In conclusion, the cardiac TWEAK/Fn14 pathway is modified in response to myocardial injury, inflammation and pressure overload. Furthermore, our findings underscore the importance of Fn14 as a mediator of TWEAK/Fn14 signalling in the heart and a potential target for therapeutic interventions.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, Biocenter Oulu, Oulu, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Mustonen
authors.forename: H
authors.initials: H
authors.lastname: Säkkinen
authors.forename: H
authors.initials: H
authors.lastname: Tokola
authors.forename: E
authors.initials: E
authors.lastname: Isopoussu
authors.forename: J
authors.initials: J
authors.lastname: Aro
authors.forename: H
authors.initials: H
authors.lastname: Leskinen
authors.forename: H
authors.initials: H
authors.lastname: Ruskoaho
authors.forename: J
authors.initials: J
authors.lastname: Rysä
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D015870:Gene Expression; D007249:Inflammation / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D051017:Apoptosis Regulatory Proteins; D000074049:Cytokine TWEAK; D008565:Membrane Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613300:Tnfrsf12a protein, rat; C497771:Tnfsf12 protein, rat; D048069:Tumor Necrosis Factors; D000804:Angiotensin II; D048051:p38 Mitogen-Activated Protein Kinases; D019808:Losartan