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Effects of selexipag and its active metabolite in contrasting the profibrotic myofibroblast activity in cultured scleroderma skin fibroblasts
- Source :
- Arthritis Research & Therapy, Vol 20, Iss 1, Pp 1-11 (2018), Arthritis Research & Therapy, ARTHRITIS RESEARCH & THERAPY
- Publication Year :
- 2018
- Publisher :
- BMC, 2018.
-
Abstract
- Background: Myofibroblasts contribute to fibrosis through the overproduction of extracellular matrix (ECM) proteins, primarily type I collagen (COL-1) and fibronectin (FN), a process which is mediated in systemic sclerosis (SSc) by the activation of fibrogenic intracellular signaling transduction molecules, including extracellular signal-regulated kinases 1 and 2 (Erk1/2) and protein kinase B (Akt). Selexipag is a prostacyclin receptor agonist synthesized for the treatment of pulmonary arterial hypertension. The study investigated the possibility for selexipag and its active metabolite (ACT-333679) to downregulate the profibrotic activity in primary cultures of SSc fibroblasts/myofibroblasts and the fibrogenic signaling molecules involved. Methods: Fibroblasts from skin biopsies obtained with Ethics Committee (EC) approval from patients with SSc, after giving signed informed consent, were cultured until the 3rd culture passage and then either maintained in normal growth medium (untreated cells) or independently treated with different concentrations of selexipag (from 30 mu M to 0.3 mu M) or ACT-333679 (from 10 mu M to 0.1 mu M) for 48 h. Protein and gene expressions of a-smooth muscle actin (alpha-SMA), fibroblast specific protein-1 (S100A4), COL-1, and FN were investigated by western blotting and quantitative real-time PCR. Erk1/2 and Akt phosphorylation was investigated in untreated and ACT-333679-treated cells by western botting. Results: Selexipag and ACT-333679 significantly reduced protein synthesis and gene expression of a-SMA, S100A4, and COL-1 in cultured SSc fibroblasts/myofibroblasts compared to untreated cells, whereas FN was significantly downregulated at the protein level. Interestingly, ACT-333679 significantly reduced the phosphorylation of Erk1/2 and Akt in cultured SSc fibroblasts/myofibroblasts. Conclusions: Selexipag and mainly its active metabolite ACT-333679 were found for the first time to potentially interfere with the profibrotic activity of cultured SSc fibroblasts/myofibroblasts at least in vitro, possibly through the downregulation of fibrogenic Erk1/2 and Akt signaling molecules.
- Subjects :
- 0301 basic medicine
lcsh:Diseases of the musculoskeletal system
Fibrosi
medicine.medical_treatment
Gene Expression
Skin fibroblast
Prostacyclin receptor agonist
Acetates
Selexipag
PATHWAY
Extracellular matrix
Systemic sclerosi
chemistry.chemical_compound
0302 clinical medicine
Prostacyclin receptor agonists, Skin fibroblasts, Fibrosis, Systemic sclerosis, Connective tissue diseases
Acetamides
Medicine and Health Sciences
Myofibroblasts
Cells, Cultured
RAT PULMONARY-ARTERY
Skin
RAYNAUDS-PHENOMENON SECONDARY
biology
Chemistry
Middle Aged
medicine.anatomical_structure
Pyrazines
Phosphorylation
Systemic sclerosis
Female
Prostacyclin receptor agonists
Skin fibroblasts
Fibrosis
Connective tissue diseases
Myofibroblast
Research Article
GROWTH-FACTOR
03 medical and health sciences
ENDOTHELIN-1
medicine
Humans
S100 Calcium-Binding Protein A4
Fibroblast
Protein kinase B
Aged
030203 arthritis & rheumatology
Scleroderma, Systemic
HYPERTENSION
Growth factor
SYSTEMIC-SCLEROSIS
ORAL ILOPROST
Muscle, Smooth
Fibroblasts
Molecular biology
Actins
Fibronectin
030104 developmental biology
biology.protein
lcsh:RC925-935
Subjects
Details
- Language :
- English
- ISSN :
- 14786362 and 14786354
- Volume :
- 20
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Arthritis Research & Therapy
- Accession number :
- edsair.doi.dedup.....68c8d552bf34ed08d62f68248f38f5ef