Serelaxin inhibits the profibrotic TGF-β1/IL-1β axis by targeting TLR-4 and the NLRP3 inflammasome in cardiac myofibroblasts

التفاصيل البيبلوغرافية
العنوان: Serelaxin inhibits the profibrotic TGF-β1/IL-1β axis by targeting TLR-4 and the NLRP3 inflammasome in cardiac myofibroblasts
المؤلفون: Anita A. Pinar, Tracey Gaspari, Felipe Tapia Cáceres, Chrishan S. Samuel
المصدر: FASEB journal : official publication of the Federation of American Societies for Experimental BiologyREFERENCES. 33(12)
سنة النشر: 2019
مصطلحات موضوعية: 0301 basic medicine, Male, Cardiac fibrosis, Inflammasomes, Interleukin-1beta, Biochemistry, Transforming Growth Factor beta1, 03 medical and health sciences, Mice, 0302 clinical medicine, In vivo, Serelaxin, Fibrosis, NLR Family, Pyrin Domain-Containing 3 Protein, Genetics, medicine, Animals, Humans, Myofibroblasts, Molecular Biology, Cells, Cultured, Relaxin, Chemistry, Myocardium, Inflammasome, medicine.disease, Molecular biology, In vitro, Recombinant Proteins, Toll-Like Receptor 4, 030104 developmental biology, Myofibroblast, 030217 neurology & neurosurgery, Biotechnology, medicine.drug
الوصف: The recombinant form of the peptide hormone relaxin, serelaxin (RLX), mediates its anti-fibrotic actions by impeding the profibrotic activity of cytokines including TGF-β1 and IL-1β. As IL-1β can be produced by the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domains-containing protein 3 (NLRP3) inflammasome, this study determined whether RLX targeted the inflammasome to inhibit the profibrotic TGF-β1/IL-1β axis in primary human cardiac myofibroblasts (HCMFs) in vitro and in mice with isoproterenol (ISO)-induced cardiomyopathy in vivo. HCMFs stimulated with TGF-β1 (5 ng/ml), LPS (100 ng/ml), and ATP (5 mM) (T+L+A) for 8 h, to induce the NLRP3 inflammasome, demonstrated significantly increased protein expression of markers of NLRP3 priming (NLRP3, apoptosis-associated speck-like protein containing a C-terminal caspase-recruitment domain, procaspase-1) and activity (IL-1β, IL-18). After 72 h, there was significantly increased neuronal NOS (nNOS), TLR-4, procaspase-1, myofibroblast differentiation, and collagen-I deposition. These measures, along with interstitial TGF-β1 expression and collagen deposition, were also increased in the left ventricle (LV) of ISO-injured mice 14 d postinjury. RLX [16.8 nM (100 ng/ml) in vitro; 0.5 mg/kg per day in vivo] inhibited T+L+A- and ISO-induced TLR-4 expression, NLRP3 priming, IL-1β, IL-18, myofibroblast differentiation, and interstitial collagen deposition at the time points studied, via the promotion of nNOS; with the NLRP3- and IL-1β-inhibitory effects of RLX in HCMFs being abrogated by pharmacological blockade of nNOS or TLR-4. Comparatively, the small molecule NLRP3 inhibitor, N-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino]carbonyl}-4-(1-hydroxy-1-methylethyl)-2-furansulfonamide (1 μM in vitro, 10 mg/kg/d in vivo), inhibited components of the NLRP3 inflammasome in vitro and in vivo and ISO-induced interstitial LV fibrosis in vivo but did not affect nNOS, TLR-4, myofibroblast differentiation, or myofibroblast-induced collagen deposition. Hence, RLX can inhibit the TGF-β1/IL-1β axis via a nNOS-TLR-4-NLRP3 inflammasome-dependent mechanism on cardiac myofibroblasts.-Caceres, F. T., Gaspari, T. A., Samuel, C. S., Pinar, A. A. Serelaxin inhibits the profibrotic TGF-β1/IL-1β axis by targeting TLR-4 and the NLRP3 inflammasome in cardiac myofibroblasts.
تدمد: 1530-6860
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d2e05f00830c752f3712c2b32682a05e
https://pubmed.ncbi.nlm.nih.gov/31689135
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....d2e05f00830c752f3712c2b32682a05e
قاعدة البيانات: OpenAIRE