Abrogation of TGF-beta1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no known effective pharmacological therapy. The fibroblastic foci of IPF contain activated myofibroblasts that are the major synthesizers of type I collagen. Transforming growth factor (TGF)-beta1 promotes differentiation of fibroblasts into myofibroblasts in vitro and in vivo. In the current study, we investigated the molecular link between TGF-beta1-mediated myofibroblast differentiation and histone deacetylase (HDAC) activity. Treatment of normal human lung fibroblasts (NHLFs) with the pan-HDAC inhibitor trichostatin A (TSA) inhibited TGF-beta1-mediated alpha-smooth muscle actin (alpha-SMA) and alpha1 type I collagen mRNA induction. TSA also blocked the TGF-beta1-driven contractile response in NHLFs. The inhibition of alpha-SMA expression by TSA was associated with reduced phosphorylation of Akt, and a pharmacological inhibitor of Akt blocked TGF-beta1-mediated alpha-SMA induction in a dose-dependent manner. HDAC4 knockdown was effective in inhibiting TGF-beta1-stimulated alpha-SMA expression as well as the phosphorylation of Akt. Moreover, the inhibitors of protein phosphatase 2A and 1 (PP2A and PP1) rescued the TGF-beta1-mediated alpha-SMA induction from the inhibitory effect of TSA. Together, these data demonstrate that the differentiation of NHLFs to myofibroblasts is HDAC4 dependent and requires phosphorylation of Akt.
Guo
Weichao
W
Biomedical Sciences Program, 1430 Tulane Ave. SL-9, Tulane Medical School, New Orleans, LA 70112, USA.
Shan
Bin
B
Klingsberg
Ross C
RC
Qin
Xiangmei
X
Lasky
Joseph A
JA
D000199:Actins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002461:Cell Line, Transformed; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
D000199:Actins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; C012589:trichostatin A; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
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