Indazole-Cl inhibits hypoxia-induced cyclooxygenase-2 expression in vascular smooth muscle cells

in Journal of Molecular Endocrinology
Correspondence should be addressed to Y Lee: yjlee@sejong.ac.kr
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Atherosclerosis is the most common root cause of arterial disease, such as coronary artery disease and carotid artery disease. Hypoxia is associated with the formation of macrophages and increased inflammation and is known to be present in lesions of atherosclerotic. Vascular smooth muscle cells (VSMCs) are one of the major components of blood vessels, and hypoxic conditions affect VSMC inflammation, proliferation and migration, which contribute to vascular stenosis and play a major role in the atherosclerotic process. Estrogen receptor (ER)-β is thought to play an important role in preventing the inflammatory response in VSMCs. In this report, we studied the anti-inflammatory effect of indazole (In)-Cl, an ERβ-specific agonist, under conditions of hypoxia. Expression of cyclooxygenase-2 reduced by hypoxia was inhibited by In-Cl treatment in VSMCs, and this effect was antagonized by an anti-estrogen compound. Additionally, the production of reactive oxygen species induced under conditions of hypoxia was reduced by treatment with In-Cl. Increased cell migration and invasion by hypoxia were also dramatically decreased following treatment with In-Cl. The increase in cell proliferation following treatment with platelet-derived growth factor was attenuated by In-Cl in VSMCs. RNA sequencing analysis was performed to identify changes in inflammation-related genes following In-Cl treatment in the hypoxic state. Our results suggest that ERβ is a potential therapeutic target for the suppression of hypoxia-induced inflammation in VSMCs.

 

      Society for Endocrinology

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    Indazole (In)-Cl inhibits hypoxia-induced cyclooxygenase (COX)-2 transcriptional activity in vascular smooth muscle cells (VSMCs). (A) VSMCs were pretreated with In-Cl (0.1 μM) and/or ICI (1 μM) for 1 h prior to treatment under hypoxic conditions for 24 h and analysis by western blotting. (B) VSMCs were pretreated with In-Cl (0.1 μM) for 1 h before treatment under hypoxic conditions for 16 h and analysis by real-time PCR. (C) VSMCs were transfected with a COX-2-Luc reporter and treated with In-Cl (10 μM) for 24 h. (D) VSMCs were transfected with an NF-κB-Luc reporter. Cells were treated with In-Cl (10 μM) and incubated for 24 h. All experiments were repeated at least three times.

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    In-Cl decreases reactive oxygen species (ROS) levels under conditions of hypoxia. VSMCs were incubated under conditions of hypoxia following pre-treatment with In-Cl (0.1 μM) for 3 h. ROS levels were measured by flow cytometry. VSMCs were treated with 1 μM DCF-DA for 15 min. All experiments were repeated at least three times.

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    In-Cl inhibits hypoxia-induced cellular migration and invasion of VSMCs. (A) VSMCs were treated with 1 μM In-Cl and/or 1 μM ICI. Transwell migration assays were conducted under conditions of hypoxia or normoxia. (B) VSMCs were treated with 5 μM celecoxib and/or 0.1 μM In-Cl and incubated under hypoxia for 24 h. Cell migration was determined using a transwell migration assay. (C) VSMCs were untreated or treated with In-Cl (0.1 μM), incubated for 48 h under hypoxic conditions, and invasion was assessed using Matrigel-coated transwell chambers. Translocated cells are visible on the lower surface of the filter. Migrating and invading cells were counted and are shown in the graph. All experiments were repeated at least two times.

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    In-Cl regulates proliferation of VSMCs. (A) VSMCs were plated on a 96-well plate. Cells were pretreated with In-Cl (0.1 μM) for 6 h and cultured with or without platelet-derived growth factor (PDGF)-BB (20 ng/mL). Cell proliferation was measured using the MTT assay. All experiments were repeated at least three times. (B) Heat map analysis of known cell proliferation-related genes regulated by ERβ agonists (In-Cl and DPN) in VSMCs. The blue bands indicate reduced gene expression; the red bands indicate increased gene expression.

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    Hierarchical clustering and Venn diagram of differentially expressed genes (DEGs) following treatment with ER ligands under hypoxic conditions. (A) Venn diagram showing the overlap between DEGs following treatment with ERβ ligand under hypoxic conditions. (B) Enriched GO terms among the transcripts significantly regulated by In-Cl or E2 in hypoxia. REVIGO uses multi-dimensional scaling of the dimensionality of a matrix of GO terms with pairwise semantic similarities. This results in semantically similar GO terms remaining close together in the plot. (C) Hierarchical clustering of DEGs using RNA sequencing data derived from VSMCs treated with ER ligands (In-Cl, DPN and E2) in a hypoxic state.

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