The Angiotensin-Converting Enzyme 2/Angiotensin (1–7)/Mas Axis Protects Against Lung Fibroblast Migration and Lung Fibrosis by Inhibiting the NOX4-Derived ROS-Mediated RhoA/Rho Kinase Pathway

Autor: Wei Li, Xu Li, Ying Meng, Miao-Xia Pang, Wenyong Zhang, Chang-Hui Yu, Gao-su Zhou, Yan Chen, Ting Li, Yang Li
Rok vydání: 2015
Předmět:
Male
medicine.medical_specialty
RHOA
Physiology
Pulmonary Fibrosis
Clinical Biochemistry
Peptidyl-Dipeptidase A
Biology
Proto-Oncogene Mas
Biochemistry
Collagen Type I
Receptors
G-Protein-Coupled
Fibroblast migration
Cell Movement
Proto-Oncogene Proteins
Internal medicine
Pulmonary fibrosis
medicine
Animals
Rats
Wistar
Molecular Biology
Rho-associated protein kinase
Cells
Cultured
General Environmental Science
rho-Associated Kinases
NADPH oxidase
NADPH Oxidases
NOX4
Cell Biology
Fibroblasts
medicine.disease
Angiotensin II
Peptide Fragments
Cell biology
Collagen Type I
alpha 1 Chain
Original Research Communications
Endocrinology
NADPH Oxidase 4
Angiotensin-converting enzyme 2
cardiovascular system
biology.protein
General Earth and Planetary Sciences
Angiotensin-Converting Enzyme 2
Angiotensin I
Reactive Oxygen Species
rhoA GTP-Binding Protein
hormones
hormone substitutes
and hormone antagonists
Zdroj: Antioxidants & Redox Signaling. 22:241-258
ISSN: 1557-7716
1523-0864
DOI: 10.1089/ars.2013.5818
Popis: Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1–7) [Ang(1–7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear. Aims: To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway. Results: In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and α-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 RNA interference. Moreover, Ang(1–7) and lentivirus-mediated ACE2 (lentiACE2) suppressed AngII-induced migration and α-collagen I synthesis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. However, Ang(1–7) alone exerted analogous effects on AngII. In vivo, constant infusion with Ang(1–7) or intratracheal instillation with lenti-ACE2 shifted the RAS balance toward the ACE2/Ang(1–7)/Mas axis, alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS. Innovation: This study suggests that the ACE2/Ang(1–7)/Mas axis may be targeted by novel pharmacological antioxidant strategies to treat lung fibrosis induced by AngII-mediated ROS. Conclusion: The ACE2/Ang(1–7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. Antioxid. Redox Signal. 22, 241–258.
Databáze: OpenAIRE
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