期刊
FASEB JOURNAL
卷 29, 期 8, 页码 3160-3170出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-268136
关键词
fibrosis; RasGrf1; transendothelial migration
资金
- U.S. National Institutes of Health National Heart, Lung, and Blood Institute [R01HL089792]
- Medallion Foundation grant
- Hankamer Foundation
Fibrosis in the oldmouse heart arises partly as a result of aberrant mesenchymal fibroblast activation. We have previously shown that endogenous mesenchymal stem cells (MSCs) in the aged heart are markedly resistant to TGF-beta signaling. Fibroblasts originating from these MSCs retain their TGF-beta unresponsiveness and become inflammatory. In current studies, we found that these inflammatory fibroblasts secreted higher levels of IL-6 (3-fold increase, P < 0.05) when compared with fibroblasts derived from the young hearts. Elevated IL-6 levels in fibroblasts derived from old hearts arose from upregulated expression of Ras protein-specific guanine nucleotide releasing factor 1 (RasGrf1), a Ras activator (5-fold, P < 0.01). Knockdown of RasGrf1 by gene silencing or pharmacologic inhibition of farnesyltransferase (FTase) or ERK caused reduction of IL-6 mRNA (more than 65%, P < 0.01) and decreased levels of secreted IL-6 (by 44%, P < 0.01). In vitro, IL-6 markedly increased monocyte chemoattractant protein-1-driven monocyte-to-myeloid fibroblast formation after transendothelial migration (TEM; 3-fold, P < 0.01). In conclusion, abnormal expression of RasGrf1 promoted production of IL-6 by mesenchymal fibroblasts in the old heart. Secreted IL-6 supported conversion of monocyte into myeloid fibroblasts. This process promotes fibrosis and contributes to the diastolic dysfunction in the aging heart.
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