Minocycline Exerts Multiple Inhibitory Effects on Vascular Endothelial Growth Factor–Induced Smooth Muscle Cell Migration

Abstract

Abstract-Widely used tetracycline antibiotics affect many cellular functions relevant to human vascular disease including cell proliferation, migration, and matrix remodeling. We examined whether minocycline inhibited human aortic smooth muscle cell (HASMC) migration induced by vascular endothelial growth factor (VEGF). After the establishment of an optimal dose, minocycline treated HASMC were exposed to VEGF. HASMC migration, matrix metalloproteinase (MMP)-2 and MMP-9 activities, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) phosphorylation were determined by smooth muscle cell (SMC) invasion assay, real-time polymerase chain reaction, zymograms, and Western blot analysis, respectively. We demonstrated that VEGF and platelet-derived growth factor (PDGF)-induced SMC migration in a dose-dependent manner. MMP-9, but not MMP-2, mRNA was increased during VEGF stimulation. MMP-9 activity was increased from 1.5-to 2.5-fold in a dose-dependent manner (PϽ0.05). Both ERK1/2 and PI3K/AKt pathways were activated during VEGF-induced HASMCs migration. We then demonstrated that minocycline can inhibit VEGF-induced HASMC migration (PϽ0.05). The effects may be through the inhibition of MMP-9 mRNA transcription, protein activities and downregulation of ERK1/2 and PI3K/Akt pathway phosphorylation. Our results indicated that minocycline exerts multiple effects on VEGF-induced SMC migration, including inhibition of MMP-9 mRNA transcription and protein activities and downregulating ERK1/2 and PI3K signal pathways, suggesting minocycline may be a potentially therapeutic approach to inhibit disease process induced angiogenesis.

Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway

“…Nakashio et al (2002) found that PI3K-Akt was downregulated during topotecan-mediated inhibition of endothelial cell angiogenesis. Yao et al (2004) similarly demonstrated that minocycline exerted its inhibitory effect on angiogenesis by suppressing MMP-9 mRNA transcription and downregulating ERK1/2 and PI3K/ Akt signal pathways. O-charoenrat et al (2004) showed that beta-cellulin induced MMP-9 production and invasion in head-and-neck squamous carcinoma cells through activation of EGFR, MAPK and PI3K/Akt.…”

Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: The role for KDR and MMP-9

“…The method of Zymographic assay was performed as described previously [15]. A 70 μg sample protein was separated under non-reducing conditions in a 10% zymogram gel (Invitrogen, Carlsbad, CA) containing 0.1% gelatin as a substrate.…”

Impact of Insulin-like Growth Factor-I on Migration, Proliferation and Akt-ERK Signaling in Early and Late-passages of Vascular Smooth Muscle Cells

“…In order to explore possible mechanisms of life cycle-associated changes in VSMC migration and proliferation, our present study was designed to examine the basal and IGF-1-stimulated migration, proliferation, and ROS formation in the early and late-passages of VSMCs. Considering the essential roles of Akt and extracellular signal-related kinase (ERK) in cell proliferation and migration [26,27], basal, and IGF-1-stilmuated phosphorylation of Akt and ERK were also assessed in these cells.…”