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Matrix metalloproteinase-2-induced epidermal growth factor receptor transactivation impairs redox balance in vascular smooth muscle cells and facilitates vascular contraction.
Prado, Alejandro F; Pernomian, Laena; Azevedo, Aline; Costa, Rute A P; Rizzi, Elen; Ramos, Junia; Paes Leme, Adriana F; Bendhack, Lusiane M; Tanus-Santos, Jose E; Gerlach, Raquel F.
Afiliação
  • Prado AF; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil; Laboratory of Structural Biology, Institute of Biological Sciences, Federal University of Para, Belem, PA, Brazil.
  • Pernomian L; Department of Biochemistry and Immunology, Faculty of Medicine at Ribeirao Preto, University of São Paulo, SP, Brazil.
  • Azevedo A; Department of Biomechanics, Medicine and Rehabilitation of the Locomotor System, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
  • Costa RAP; Mass Spectrometry Laboratory, Brazilian Biosciences National Laboratory, LNBio, CNPEM, Campinas, Brazil.
  • Rizzi E; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
  • Ramos J; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil; Laboratory of Structural Biology, Institute of Biological Sciences, Federal University of Para, Belem, PA, Brazil; Department of Biochemistry and Immunology, Faculty of Medicine at Ribeira
  • Paes Leme AF; Mass Spectrometry Laboratory, Brazilian Biosciences National Laboratory, LNBio, CNPEM, Campinas, Brazil.
  • Bendhack LM; Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences from Ribeirao Preto, University of São Paulo, Ribeirao Preto, SP, Brazil.
  • Tanus-Santos JE; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
  • Gerlach RF; Department of Morphology, Physiology and Basic Pathology, Faculty of Dentistry of Ribeirao Preto, University of Sao Paulo, Av. Café, S/N - Ribeirao Preto, SP 14040-904, Brazil. Electronic address: rfgerlach@forp.usp.br.
Redox Biol ; 18: 181-190, 2018 09.
Article em En | MEDLINE | ID: mdl-30029165
Increased reactive oxygen species (ROS) formation may enhance matrix metalloproteinase (MMP)-2 activity and promote cardiovascular dysfunction. We show for the first time that MMP-2 is upstream of increased ROS formation and activates signaling mechanisms impairing redox balance. Incubation of vascular smooth muscle cells (VSMC) with recombinant MMP-2 increased ROS formation assessed with dihydroethidium (DHE) by flow cytometry. This effect was blocked by the antioxidant apocynin or by polyethylene glycol-catalase (PEG-catalase), and by MMP inhibitors (doxycycline or GM6001). Next, we showed in HEK293 cells that MMP-2 transactivates heparin-binding epidermal growth factor (HB-EGF) leading to EGF receptor (EGFR) activation and increased ROS concentrations. This effect was prevented by the EGFR kinase inhibitor Ag1478, and by phospholipase C (PLC) or protein kinase C (PKC) inhibitors (A778 or chelerythrine, respectively), confirming the involvement of EGFR pathway in MMP-2-induce responses. Next, we showed that intraluminal exposure of aortas to MMP-2 increased vascular MMP-2 levels detected by immunofluorescence and gelatinolytic activity (by in situ zimography) in association with increased ROS formation. This effect was inhibited by MMP inhibitors (phenanthroline or doxycycline) and by apocynin or PEG-catalase. MMP-2 also increased aortic contractility to phenylephrine and this effect was prevented by MMP inhibitor GM6001 and by apocynin or PEG-catalase, showing again that increased ROS formation mediates functional effects of MMP-2. These results show that MMP-2 activates the EGFR and triggers downstream signaling pathways increasing ROS formation and promoting vasoconstriction. These findings may have various implications for cardiovascular diseases.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aorta / Vasoconstrição / Ativação Transcricional / Metaloproteinase 2 da Matriz / Receptores ErbB / Músculo Liso Vascular Limite: Animals Idioma: En Revista: Redox Biol Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda
Texto completo
Adicionar na Minha BVS
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aorta / Vasoconstrição / Ativação Transcricional / Metaloproteinase 2 da Matriz / Receptores ErbB / Músculo Liso Vascular Limite: Animals Idioma: En Revista: Redox Biol Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda