The anti-inflammatory actions of LCY-2-CHO, a carbazole analogue, in vascular smooth muscle cells

LCY-2-CHO has anti-infl amm atory actions on macrophages. To understand its therapeutic implication in atherosclerosis, we examined its effects on the expressions of antiinflammatory and inflammatory proteins in cultured rat aortic vascular smooth muscle cells (VSMC). LCY-2-CHO is able to induce heme oxygenase-1 (HO-1) protein expression through a transcriptional action. The HO-1 inducting effect of LCY-2-CHO was inhibited by SB203580, N (G)-nitro-L-arginine methylester (L-NAME), and wortmannin, but was not affected by U0126 or SP600125. In accordance LCY-2-CHO increased protein phosphorylation of p38, Akt, and eNOS. Nrf2 is a transcription factor essential for HO-1 gene induction and we showed that LCY-2-CHO is able to cause Nrf2 nuclear translocation and this action depends on p38, Akt and eNOS. in addition to induce anti-inflammatory HO-1, LCY-2-CHO reduced interleukin-lp (IL-1 beta)-induced inflammatory mediators, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), growth-related oncogene protein-alpha (GRO-alpha), and interleukin-8 (IL-8). Inhibitory effect on IL-lp-mediated NF-KB activation was evidenced by the diminishment of I kappa B kinase (IKK) phosphorylation and I kappa B alpha degradation. In contrast, IL-1 beta-mediated ERK and JNK activations were not changed by LCY-2-CHO, while p38 activation by IL-1 beta and LCY-2-CHO displayed the nonadditivity. Taken together, given the overall anti-inflammatory properties of LCY-2-CHO in VSMC, in terms to induce HO-1 gene expression and inhibit inflammatory gene expression, these results highlight the therapeutic potential of LCY-2-CHO in atherosclerosis. (C) 2007 Elsevier Inc. All rights reserved.