The C-terminal module IV of connective tissue growth factor, through EGFR/Nox1 signaling, activates the NF-κB pathway and proinflammatory factors in vascular smooth muscle cells.

Rodrigues Díez, RaúlRuiz Ortega, Marta2024-02-072024-02-072015-01-01Raúl R. Rodrigues-Diez, Ana Belen Garcia-Redondo, Macarena Orejudo, Raquel Rodrigues-Diez, Ana Maria Briones, Enrique Bosch-Panadero, Gyorgy Kery, Janos Pato, Alberto Ortiz, Mercedes Salaices, Jesus Egido, and Marta Ruiz-Ortega. The C-Terminal Module IV of Connective Tissue Growth Factor, Through EGFR/Nox1 Signaling, Activates the NF-κB Pathway and Proinflammatory Factors in Vascular Smooth Muscle Cells. Antioxidants & Redox Signaling.Jan 2015.29-47.http://doi.org/10.1089/ars.2013.55001523-086410.1089/ars.2013.5500https://hdl.handle.net/20.500.14352/99905Aims: 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. Antioxid. Redox Signal. 22, 29–47.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/The C-terminal module IV of connective tissue growth factor, through EGFR/Nox1 signaling, activates the NF-κB pathway and proinflammatory factors in vascular smooth muscle cells.journal articlehttps://www.liebertpub.com/doi/full/10.1089/ars.2013.550025065408https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270131/open access576Ciencias Biomédicas24 Ciencias de la Vida