Journal
CIRCULATION
Volume 124, Issue 19, Pages 2106-U174Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.111.052399
Keywords
tumor necrosis factor; transforming growth factor beta; fibroblasts; mast cells; fibrosis
Funding
- National Institutes of Health [RO1 HL58081, RO1 HL61543, RO1 HL-42250, T32 HL007816 NIH]
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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. Methods and 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 beta 1 and type I transforming growth factor beta 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 alpha-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 beta 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. (Circulation. 2011;124:2106-2116.)
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