The development of myocardial fibrosis in transgenic mice with targeted overexpression of tumor necrosis factor requires mast cell-fibroblast interactions.
BACKGROUND
Transgenic mice with cardiac-restricted overexpression of tumor necrosis factor (MHCsTNF mice) develop progressive myocardial fibrosis, diastolic dysfunction, and adverse cardiac remodeling. Insofar as tumor necrosis factor (TNF) does not directly stimulate fibroblast collagen synthesis, we asked whether TNF-induced fibrosis was mediated indirectly through interactions between mast cells and cardiac fibroblasts.


RESULTS
Cardiac mast cell number increased 2 to 3 fold (P<0.001) in MHCsTNF mice compared with littermate controls. Outcrossing MHCsTNF mice with mast cell-deficient (c-kit(-/-)) mice showed that the 11-fold increase (P<0.001) in collagen volume fraction in MHCsTNF/c-kit(+/-) mice was abrogated in MHCsTNF/c-kit(-/-) mice, and that the leftward shifted left ventricular pressure-volume curve in the MHCsTNF/c-kit(+/-) mice was normalized in the MHCsTNF/c-kit(-/-) hearts. Furthermore, the increase in transforming growth factor β1 and type I transforming growth factor β receptor messenger RNA levels was significantly (P=0.03, P=0.01, respectively) attenuated in MHCsTNF/c-kit(-/-) when compared with MHCsTNF/c-kit(+/-) mice. Coculture of fibroblasts with mast cells resulted in enhanced α-smooth muscle actin expression, increased proliferation and collagen messenger RNA expression, and increased contraction of 3-dimensional collagen gels in MHCsTNF fibroblasts compared with littermate fibroblasts. The effects of mast cells were abrogated by type I transforming growth factor β receptor antagonist NP-40208.


CONCLUSIONS
These results suggest that increased mast cell density with resultant mast cell-cardiac fibroblast cross-talk is required for the development of myocardial fibrosis in inflammatory cardiomyopathy. Cardiac fibroblasts exposed to sustained inflammatory signaling exhibit an increased repertoire of profibrotic phenotypic responses in response to mast cell mediators.
Division of Cardiology, Washington University School of Medicine, 660 S Euclid Avenue, St. Louis, MO 63110, USA. .
Weili
W
Zhang
Amanda L
AL
Chancey
Huei-Ping
HP
Tzeng
Zhenqing
Z
Zhou
Kory J
KJ
Lavine
Feng
F
Gao
Natarajan
N
Sivasubramanian
Philip M
PM
Barger
Douglas L
DL
Mann
D000818:Animals; D002450:Cell Communication / Q000276:immunology*; D004719:Endomyocardial Fibrosis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology*; D015870:Gene Expression / Q000276:immunology; D008407:Mast Cells / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D061251:Primary Cell Culture; D011621:Pteridines / Q000494:pharmacology; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
C529989:NP 40208; D011621:Pteridines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha