Rho-GDP dissociation inhibitor alpha downregulated by low shear stress promotes vascular smooth muscle cell migration and apoptosis: a proteomic analysis

Aims Low shear stress (LSS) plays a significant role in vascular remodelling during atherogenesis, which involves migration, proliferation, and apoptosis of vascular smooth muscle cells (VSMCs). The aim of the present study is to elucidate the molecular mechanisms by which LSS induces vascular remodelling. Methods and results Using proteomic techniques, two-dimensional electrophoresis, and mass spectrometry, the protein profiles of Sprague-Dawley rat aorta cultured under two levels of shear stress, 5 and 15 dyn/cm(2), were determined. The results showed a significantly lower expression of protein-Rho-GDP dissociation inhibitor alpha (Rho-GDI alpha) in the LSS vessels. Rho-GDI alpha signalling mechanisms and effects on VSMC migration and apoptosis were then studied to understand the role of Rho-GDI alpha in the LSS-induced vascular remodelling. A decrease in Rho-GDI alpha expression by using target small interfering RNA (siRNA) transfection caused increases in the phosphorylation of Rac1 and Akt and enhancements of VSMC migration and apoptosis. Treatment with the PI3K/Akt-specific inhibitor wortmannin significantly decreased Akt phosphorylation, but had no effect on Rho-GDI alpha expression and Rac1 phosphorylation. Wortmannin was able to reverse the Rho-GDI alpha siRNA-induced enhancement of VSMC migration, but not VSMC apoptosis. Conclusion The results indicate that the LSS-induced VSMC migration and apoptosis are mediated by a downregulation of Rho-GDI alpha. The effect of Rho-GDI alpha on VSMC migration is mediated by the PI3K/Akt pathway, but its effect on VSMC apoptosis is not.