The C-Terminal module IV of connective tissue growth factor, through EGFR/Nox1 signaling, activates the NF-jB pathway and proinflammatory factors in vascular smooth muscle cells
Entity
UAM. Departamento de MedicinaPublisher
Mary Ann LiebertDate
2015Citation
10.1089/ars.2013.5500
Antioxidants and Redox Signaling 22.1 (2015): 29-47
ISSN
1557-7716 (online); 1523-0864 (print)DOI
10.1089/ars.2013.5500Subjects
MedicinaRights
© Mary Ann Liebert, IncAbstract
Connective tissue growth factor (CTGF/CCN2) is a developmental gene upregulated in pathological conditions, including cardiovascular diseases, whose product is a matricellular protein that can be degraded to biologically active fragments. Among them, the C-terminal module IV [CCN2(IV)] regulates many cellular functions, but there are no data about redox process. Therefore, we investigated whether CCN2(IV) through redox signaling regulates vascular responses. Results: CCN2(IV) increased superoxide anion (O2(•-)) production in murine aorta (ex vivo and in vivo) and in cultured vascular smooth muscle cells (VSMCs). In isolated murine aorta, CCN2(IV), via O2(•-), increased phenylephrine-induced vascular contraction. CCN2(IV) in vivo regulated several redox-related processes in mice aorta, including increased nonphagocytic NAD(P)H oxidases (Nox)1 activity, protein nitrosylation, endothelial dysfunction, and activation of the nuclear factor-κB (NF-κB) pathway and its related proinflammatory factors. The role of Nox1 in CCN2(IV)-mediated vascular responses in vivo was investigated by gene silencing. The administration of a Nox1 morpholino diminished aortic O2(•-) production, endothelial dysfunction, NF-κB activation, and overexpression of proinflammatory genes in CCN2(IV)-injected mice. The link CCN2(IV)/Nox1/NF-κB/inflammation was confirmed in cultured VSMCs. Epidermal growth factor receptor (EGFR) is a known CCN2 receptor. In VSMCs, CCN2(IV) activates EGFR signaling. Moreover, EGFR kinase inhibition blocked vascular responses in CCN2(IV)-injected mice. Innovation and conclusion: CCN2(IV) is a novel prooxidant factor that in VSMCs induces O2(•-) production via EGFR/Nox1 activation. Our in vivo data demonstrate that CCN2(IV) through EGFR/Nox1 signaling pathway induces endothelial dysfunction and activation of the NF-κB inflammatory pathway. Therefore, CCN2(IV) could be considered a potential therapeutic target for redox-related cardiovascular diseases
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Google Scholar:Rodrigues-Diez, Raul R.
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García Redondo, Ana Belén
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Orejudo, Macarena
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Rodrigues Díez, Raquel
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Briones Alonso, Ana María
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Bosch-Panadero, Enrique
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Keri, Gyorgy
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Pato, Janos
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Ortiz Arduán, Alberto
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Salaices Sánchez, Mercedes
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Egido, Jesus
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Ruiz Ortega, Marta
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