Fernandez I, Martin-Garrido A, Zhou DW, Clempus RE, Seidel-Rogol B, Valdivia A, Lassegue B, Garcia AJ, Griendling KK, San Martin A

Focal adhesions (FAs) link the cytoskeleton to the extracellular matrix and as such play important roles in growth, migration, and contractile properties of vascular smooth muscle cells. Recently, it has been shown that downregulation of Nox4, a transforming growth factor (TGF) ?-inducible, hydrogen peroxide (H2O2)-producing enzyme, affects the number of ...

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FAs. However, the effectors downstream of Nox4 that mediate FA regulation are unknown. The FA resident protein H2O2-inducible clone (Hic)-5 is H2O2 and TGF? inducible, and a binding partner of the heat shock protein (Hsp) 27. The objective of this study was to elucidate the mechanism, by which Hic-5 and Hsp27 participate in TGF?-induced, Nox4-mediated vascular smooth muscle cell adhesion and migration.Through a combination of molecular biology and biochemistry techniques, we found that TGF?, by a Nox4-dependent mechanism, induces the expression and interaction of Hic-5 and Hsp27, which is essential for Hic-5 localization to FAs. Importantly, we found that Hic-5 expression is required for the TGF?-mediated increase in FA number, adhesive forces and migration. Mechanistically, Nox4 downregulation impedes Smad (small body size and mothers against decapentaplegic) signaling by TGF?, and Hsp27 and Hic-5 upregulation by TGF? is blocked in small body size and mothers against decapentaplegic 4-deficient cells.Hic-5 and Hsp27 are effectors of Nox4 required for TGF?-stimulated FA formation, adhesion strength and migration in vascular smooth muscle cell.

Date: May. 01, 2015

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