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

Abstract

LCY-2-CHO has anti-inflammatory actions on macrophages. To understand its therapeutic implication in atherosclerosis, we examined its effects on the expressions of anti-inflammatory 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-1beta (IL-1beta)-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-1beta-mediated NF-kappaB activation was evidenced by the diminishment of IkappaB kinase (IKK) phosphorylation and IkappaBalpha degradation. In contrast, IL-1beta-mediated ERK and JNK activations were not changed by LCY-2-CHO, while p38 activation by IL-1beta and LCY-2-CHO displayed the non-additivity. 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.

• Authors: Feng-Ming Ho, Hao-Cheng Kang, Sho-Tone Lee, Yee Chao, You-Ci Chen, Li-Jiau Huang, Wan-Wan Lin
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 74 Issue 2 Pg. 298-308 (Jul 15 2007) ISSN: 0006-2952 [Print] England
• PMID: 17499220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 9-(2-chlorobenzyl)-9H-carbazole-3-carbaldehyde
• Anti-Inflammatory Agents
• Carbazoles
• Chemokine CXCL1
• Chemokines, CXC
• Cxcl1 protein, rat
• Interleukin-1beta
• NF-E2-Related Factor 2
• Nitric Oxide Synthase Type II
• Heme Oxygenase (Decyclizing)
• Hmox1 protein, rat

Topics

• Active Transport, Cell Nucleus (drug effects)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Carbazoles (pharmacology)
• Cell Survival (drug effects)
• Cells, Cultured
• Chemokine CXCL1
• Chemokines, CXC (biosynthesis)
• Gene Expression Regulation (drug effects)
• Heme Oxygenase (Decyclizing) (genetics)
• Interleukin-1beta (pharmacology)
• Muscle, Smooth, Vascular (cytology, drug effects, metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Nitric Oxide Synthase Type II (biosynthesis)
• Rats
• Signal Transduction (drug effects)
• Transcriptional Activation