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NAD(P)H oxidase-derived reactive oxygen species regulate angiotensin-II induced adventitial fibroblast phenotypic differentiation

Shanghai Jiao Tong University, Shanghai, Shanghai Shi, China
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 02/2006; 339(1):337-43. DOI: 10.1016/j.bbrc.2005.10.207
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ABSTRACT Phenotypic differentiation of adventitial fibroblasts into myofibroblasts is an essential feature of vascular remodeling. The present study was undertaken to test the hypothesis that reactive oxygen species (ROS) are involved in rat adventitial fibroblast differentiation to myofibroblast. Activation of alpha-smooth muscle actin (alpha-SMA) was used as a marker of myofibroblast. Angiotensin II increased intracellular ROS in adventitial fibroblasts that was completely inhibited by the free radical scavenger NAC, the NAD(P)H oxidase inhibitor DPI, and transfection of antisense gp91phox oligonucleotides. Myofibroblast differentiation was prevented by inhibition of ROS generation with DPI, NAC, and antisense gp91phox as shown by decreased expression of alpha-SMA. Angiotensin II rapidly induced phosphorylation of p38 MAPK and JNK, both of which were inhibited by DPI, NAC, antisense gp91phox, and the selective AT1 receptor antagonist, losartan. Inhibiting p38MAPK with SB202190 or JNK with SP600125 also reduced angiotensin II-induced alpha-SMA expression. These findings demonstrate that angiotensin II induces adventitial fibroblast differentiation to myofibroblast via a pathway that involves NADPH oxidase generation of ROS and activation of p38MAPK and JNK pathways.

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    • "In fibroblasts of adventitia from vascular cells, ROS generated by NAD(P)H oxidase, activated the MAPK and finally the fibroblasts differentiated to MFs [30]. To check the importance of MAPK during the transition process of HDF, HDF were exposed to rTGFβ1 in the presence and absence of non-toxic concentration of U0126, SP600125 and SB202190 (10 μM). "
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    Bioscience Reports 12/2013; 34(1). DOI:10.1042/BSR20130091 · 2.85 Impact Factor
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    • "We previously showed that Ang II activates MAPKs in adventitial fibroblasts [19]. Therefore, we examined whether the MAPK activation was involved in Ang II–induced OPN expression in adventitial fibroblasts. "
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    • "Annexin A1 has been shown to modulate ERK but not p38 or JNK activity in lipopolysaccharride-induced responses20 and regulate cell proliferation by disruption of cell morphology and inhibition of cyclin D1 expression through sustained activation of the ERK1/2 MAPK pathway21. Our previous studies showed that ERK1/2 was activated during phenotypic differentiation of AFs into MFs22 and migration induced by Ang II23. Moreover, annexin A1 is a substrate for protein kinase C (PKC) and protein tyrosine kinases and has multiple phosphorylation sites as well as calcium and phospholipid binding properties. "
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