The lignan (+)-episesamin interferes with TNF-α-induced activation of VSMC via diminished activation of NF-κB, ERK1/2 and AKT and decreased activity of gelatinases

AimActivation of vascular smooth muscle cells (VSMC), a key event in the pathogenesis of atherosclerosis, is triggered by inflammatory stimuli such as tumour necrosis factor-alpha (TNF-) causing a mitogenic VSMC response. The polyphenol (+)-episesamin (ES) was shown to counteract TNF--induced effects, for example in macrophages. Aiming for novel therapeutic options, we here investigated whether ES protects VSMC from TNF--induced growth and migration, which both contribute to the onset and progression of atherosclerosis. MethodsHuman and murine VSMC were treated with combinations of ES and TNF-. Expressions of mRNA were analyzed by RT-PCR. Enzymatic activities and proliferation were determined by specific substrate assays. Cell signalling was analyzed by Western blot and reporter gene assays. Migration was assessed by wound healing assays. ResultsES at 1-10m reduced basal and TNF--induced VSMC proliferation and migration due to impaired activation of extracellular signal-regulated kinases (ERK)1/2, Akt (protein kinase B), nuclear factor-kappa B (NF-?B) and vascular cell adhesion molecule (VCAM)-1. This was accompanied by reduced expression and secretion of matrix metalloproteinases (MMP)-2/-9, which are known to promote VSMC migration. Specific inhibitors of Akt, NF-?B and MMP-2/-9 reduced TNF--induced VSMC proliferation, confirming ES-specific effects. Besides, ES reduced TNF-- and H2O2-induced oxidative stress and in parallel induces anti-inflammatory haem oxygenase (HO)-1 expression. ConclusionES interferes with inflammation-associated VSMC activation and subsequent decreased proliferation and migration due to anti-oxidative properties and impaired activation of NF-?B, known contributors to atherogenesis. These results suggest ES as a complemental treatment of VSMC specific vascular diseases such as atherosclerosis.