Grape seed proanthocyanidins attenuate vascular smooth muscle cell proliferation via blocking phosphatidylinositol 3-kinase-dependent signaling pathways.

The excess generation of reactive oxygen species (ROS) play important role in the development and progression of diabetes and related vascular complications. Therefore, blocking the production of ROS will be able to improve hyperglycemia-induced vascular dysfunction. The objective of this study was to determine whether a novel IH636 grape seed proanthocyanidins (GSPs) could protect against hyperproliferation of cultured rat vascular smooth muscle cells (VSMCs) induced by high glucose (HG) and determine the related molecular mechanisms. Our data demonstrated that GSPs markedly inhibited rat VSMCs proliferation as well as ROS generation and NAPDH oxidase activity induced by HG treatment. Further studies revealed that HG treatment resulted in phosphorylation and membrane translocation of Rac1, p47phox, and p67phox subunits leading to NADPH oxidase activation. GSPs treatment remarkably disrupted the phosphorylation and membrane translocation of Rac1, p47phox, and p67phox subunits. More importantly, our data further revealed that GSPs significantly disrupted HG-induced activation of ERK1/2, JNK1/2, and PI3K/AKT/GSK3beta as well as NF-kappaB signalings, which were dependent on reactive oxygen species (ROS) generation and Rac1 activation. In addition, our results also demonstrated that HG-induced cell proliferation and excess ROS production was dependent on the activation of PI3 kinase subunit p110alpha. Collectively, these results suggest that HG-induced VSMC growth was attenuated by grape seed proanthocyanidin (GSPs) treatment through blocking PI3 kinase-dependent signaling pathway, indicating that GSPs may be useful in retarding intimal hyperplasia and restenosis in diabetic vessels.