NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts

Human cardiac fibroblasts are the main source of cardiac fibrosis associated with cardiac hypertrophy and heart failure. Transforming growth factor-beta1 (TGF-beta1) irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin (SM alpha-actin) de novo a...

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Published in:Circulation research 2005-10, Vol.97 (9), p.900-907
Main Authors: Cucoranu, Ioan, Clempus, Roza, Dikalova, Anna, Phelan, Patrick J, Ariyan, Srividya, Dikalov, Sergey, Sorescu, Dan
Format: Article
Language:English
Subjects:
Actins - genetics
Cell Differentiation - drug effects
Cells, Cultured
Connective Tissue Growth Factor
Fibroblasts - metabolism
Fibroblasts - pathology
Fibrosis
Humans
Immediate-Early Proteins - genetics
Intercellular Signaling Peptides and Proteins - genetics
Myocardium - metabolism
Myocardium - pathology
NADPH Oxidase 4
NADPH Oxidases - genetics
NADPH Oxidases - physiology
Reactive Oxygen Species
RNA, Messenger - analysis
Smad2 Protein - physiology
Smad3 Protein - physiology
Superoxides - metabolism
Transforming Growth Factor beta - pharmacology
Transforming Growth Factor beta1
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Summary:Human cardiac fibroblasts are the main source of cardiac fibrosis associated with cardiac hypertrophy and heart failure. Transforming growth factor-beta1 (TGF-beta1) irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin (SM alpha-actin) de novo and produce extracellular matrix. We hypothesized that TGF-beta1-stimulated conversion of fibroblasts to myofibroblasts requires reactive oxygen species derived from NAD(P)H oxidases (Nox). We found that TGF-beta1 potently upregulates the contractile marker SM alpha-actin mRNA (7.5+/-0.8-fold versus control). To determine whether Nox enzymes are involved, we first performed quantitative real time polymerase chain reaction and found that Nox5 and Nox4 are abundantly expressed in cardiac fibroblasts, whereas Nox1 and Nox2 are barely detectable. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated by 16.2+/-0.8-fold (n=3, P
ISSN:1524-4571