title: Angiotensin II induces MMP 2 activity via FAK/JNK pathway in human endothelial cells.
abstract: Matrix metalloproteinases (MMPs) play an important role in the pathogenesis of cardiovascular diseases and are modified in response to a variety of stimuli such as bioactive peptides, cytokines and/or grown factors. In this study, we demonstrated that angiotensin II (Ang II) induces a time- and dose-dependent increase in the activity of metalloproteinase 2 (MMP 2) in human umbilical vein endothelial cells (HUVEC). The effect of Ang II was markedly attenuated in cells pretreated with wortmannin and LY294002, two selective inhibitors of phosphatidylinositol-3-kinase (PI3K), indicating that PI3K plays a key role in regulating MMP 2 activity. Similar results were observed when HUVEC were pretreated with genistein, a non-selective tyrosine kinases inhibitor, or with the specific Src-family tyrosine kinase inhibitor PP2, demonstrating the involvement of protein tyrosine kinases, and particularly Src-family tyrosine kinases on the downstream signaling pathway of Ang II receptors. Furthermore, Ang II-induced MMP 2 activation was markedly blocked by SP600125, a selective c-Jun N-terminal kinase (JNK) inhibitor, or pre-treatment of cells with antisense oligonucleotide to focal adhesion kinase (FAK), indicating that both molecules were important for the activation of MMP 2 by Ang II receptor stimulation. In conclusion, these results suggest that Ang II mediates an increase in MMP 2 activity in macrovascular endothelial cells through signal transduction pathways dependent on PI3K and Src-family tyrosine kinases activation, as well as JNK and FAK phosphorylation.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Málaga, Boulevard Louis Pasteur 32, 29071 Málaga, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Jiménez
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez de la Blanca
authors.forename: Loredana
authors.initials: L
authors.lastname: Urso
authors.forename: Irene
authors.initials: I
authors.lastname: González
authors.forename: Julián
authors.initials: J
authors.lastname: Salas
authors.forename: Mercedes
authors.initials: M
authors.lastname: Montiel