title: Cardiac fibroblasts support cardiac inflammation in heart failure.
abstract: Cardiac remodeling and inflammation are hallmarks of cardiac failure and correlate with outcome in patients. However, the basis for the development of both remains unclear. We have previously reported that cardiac inflammation triggers transdifferentiation of fibroblasts to myofibroblasts and therefore increase accumulation of cardiac collagen, one key pathology in cardiac remodeling. Hence, identifying key pathways for inflammation would be beneficial for patients suffering from heart failure also. Besides their well-characterized function in matrix regulation, we here investigate the role of fibroblasts in the inflammatory process. We address for the first time the role of fibroblasts as inflammatory supporter cells in heart failure. Using endomyocardial biopsies from patients with heart failure and dilated cardiomyopathy, we created a primary human cardiac fibroblast cell culture system. We found that mechanical stretch mimicking cardiac dilation in heart failure induces activation of fibroblasts and not only stimulates production of extracellular matrix but more interestingly up-regulates chemokine production and triggers typical inflammatory pathways in vitro. Moreover, the cell culture supernatant of stretched fibroblasts activates inflammatory cells and induces further recruitment of monocytes by allowing transendothelial migration into the cardiac tissue. Our findings reveal that cardiac fibroblasts provide pro-inflammatory mediators and may act as sentinel cells activated by mechanical stress. Those cells are able to recruit inflammatory cells into the cardiac tissue, a process known to aggravate outcome of patients. This might be important in different forms of heart failure and therefore may be one general mechanism specific for fibroblasts.
authors.affiliation: Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistr. 52, 20246, Hamburg, Germany, d.lindner@uke.de.
authors.forename: Diana
authors.initials: D
authors.lastname: Lindner
authors.forename: Christin
authors.initials: C
authors.lastname: Zietsch
authors.forename: Juliane
authors.initials: J
authors.lastname: Tank
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
authors.forename: Nina
authors.initials: N
authors.lastname: Fluschnik
authors.forename: Svenja
authors.initials: S
authors.lastname: Hinrichs
authors.forename: Lars
authors.initials: L
authors.lastname: Maier
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology*; D006333:Heart Failure / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000276:immunology* / Q000473:pathology*; D013314:Stress, Mechanical