Prostaglandin D2 stimulates phenotypic changes in vascular smooth muscle cells

• Published in: Experimental & molecular medicine 2019, 51(0), , pp.1-10
• Main Authors: Lee, Hye Sun, Yun, Sung Ji, Ha, Jung Min, Jin, Seo Yeon, Ha, Hong Koo, Song, Sang Heon, Kim, Chi Dae, Bae, Sun Sik
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 14/19; 14/32; 38/77; 38/89; 42/41; 631/80/86/2365; 64/60; 692/699/75/593/2100; 82/51; Antagonists; Arteriosclerosis; Biomedical and Life Sciences; Biomedicine; Carotid artery; Celecoxib; Collagen; Contraction; Cyclooxygenase-2; Genetic transformation; Inflammation; Medical Biochemistry; Molecular Medicine; Muscle contraction; Peroxisome proliferator-activated receptors; Phenotypes; Prostaglandin D2; Prostaglandins; Regulatory sequences; Reporter gene; Smooth muscle; Stem Cells; Tumor necrosis factor-α; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-019-0330-3

Since chronic inflammation is associated with the pathogenesis of atherosclerosis, inflammatory cytokines might contribute to the phenotypic modulation of vascular smooth muscle cells (VSMCs). Tumor necrosis factor α (TNFα) facilitated the transformation of contractile VSMCs to the synthetic phenotype, as determined by the expression of marker proteins and a collagen gel contraction assay. Western blot analysis and a cyclooxygenase-2 (COX2) promoter assay revealed that TNFα stimulation resulted in the induction of COX2. The overexpression, silencing, or pharmacological inhibition of COX2 significantly affected TNFα-induced phenotypic conversion, and of the tested prostaglandins, only PGD 2 significantly induced phenotypic conversion. ERK was significantly activated by PGD 2 stimulation, and the pharmacological inhibition of ERK blocked the PGD 2 -induced phenotypic conversion of VSMCs. However, antagonists or agonists of PGD 2 receptors did not affect VSMC conversion. In contrast, spontaneously dehydrated forms of PGD 2 , such as PGJ 2 , Δ 12 -PGJ 2 , and 15-d-PGJ 2 , strongly induced phenotypic conversion. A reporter gene assay showed that TNFα, PGD 2 , and 15-d-PGJ 2 significantly activated the peroxisome proliferator-responsive element (PPRE) promoter. In addition, the overexpression or silencing of peroxisome proliferator-activated receptor δ (PPARδ) significantly influenced 15-d-PGJ 2 -induced phenotypic conversion. Finally, atherosclerotic neointima formation was significantly suppressed in mice lacking TNFα. In addition, mice fed celecoxib exhibited complete inhibition of carotid artery ligation-induced neointima formation. This study shows that PGD 2 regulates the phenotypic conversion of VSMCs by generating an endogenous ligand of PPAR, and that this leads to neointima formation in occlusive arterial disease. Artherosclerosis: Switching mechanism revealed A lipid compound that stimulates muscle cells to change type is instrumental in the development of arterial plaque formation in artherosclerosis. Sun Sik Bae at Pusan National University School of Medicine in Gyungnam, South Korea, and co-workers examined the role of inflammatory proteins in the development of artherosclerosis, a condition involving the build-up of scar tissue or ‘plaques’ on artery walls. The behavior of vascular smooth muscle cells (VSMCs) is crucial to plaque development because, triggered by inflammatory protein activity, the cells switch from contractile-type cells to faster