NAD(P)H oxidase-derived reactive oxygen species regulate angiotensin-II induced adventitial fibroblast phenotypic differentiation.
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.
Shen
Wei-Li
WL
Joint laboratory of Vascular Biology of Health Science Center and Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, 225 Chong Qing South Road, Shanghai 200025, China.
Gao
Ping-Jin
PJ
Che
Zai-Qian
ZQ
Ji
Kai-Da
KD
Yin
Ming
M
Yan
Chen
C
Berk
Bradford C
BC
Zhu
Ding-Liang
DL
D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003238:Connective Tissue / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000873:Anthracenes; D016166:Free Radical Scavengers; D007093:Imidazoles; D008562:Membrane Glycoproteins; D020319:Oligodeoxyribonucleotides, Antisense; D011725:Pyridines; D017382:Reactive Oxygen Species; D000804:Angiotensin II; C432165:pyrazolanthrone; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019808:Losartan; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole