AIM: Atrial fibrosis, one of the most striking features in the pathology of atrial fibrillation (AF), is promoted by local and systemic inflammation. Electrophilic fatty acid nitroalkenes, endogenously generated by both metabolic and inflammatory reactions, are anti-inflammatory mediators that in synthetic form may be useful as drug candidates. Herein we investigate whether an exemplary nitro-fatty acid can limit atrial fibrosis and AF. METHODS AND RESULTS: Wild-type C57BL6/J mice were treated for 2 weeks with angiotensin II (AngII) and vehicle or nitro-oleic acid (10-nitro-octadec-9-enoic acid, OA-NO2, 6 mg/kg body weight) via subcutaneous osmotic minipumps. OA-NO2 significantly inhibited atrial fibrosis and depressed vulnerability for AF during right atrial electrophysiological stimulation to levels observed for AngII-naive animals. Left atrial epicardial mapping studies demonstrated preservation of conduction homogeneity by OA-NO2. The protection from fibrotic remodelling was mediated by suppression of Smad2-dependent myofibroblast transdifferentiation and inhibition of Nox2-dependent atrial superoxide formation. CONCLUSION: OA-NO2 potently inhibits atrial fibrosis and subsequent AF. Nitro-fatty acids and possibly other lipid electrophiles thus emerge as potential therapeutic agents for AF, either by increasing endogenous levels through dietary modulation or by administration as synthetic drugs.
- MeSH
- akční potenciály účinky léků MeSH
- angiotensin II farmakologie MeSH
- dusíkaté sloučeniny farmakologie MeSH
- fibrilace síní prevence a kontrola MeSH
- fibróza MeSH
- konexin 43 analýza MeSH
- kultivované buňky MeSH
- kyseliny linolové farmakologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- protein Smad2 antagonisté a inhibitory MeSH
- remodelace síní účinky léků MeSH
- srdeční síně patologie MeSH
- transdiferenciace buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Several lines of evidence suggest that in mice the activation of SMAD2/3 signaling by oocyte secreted factors, together with epidermal growth factor receptor (EGFR) activation, is essential to induce cumulus expansion. Here we show that inhibition of EGFR kinase in follicle stimulating hormone (FSH)-stimulated porcine oocyte-cumulus cell complex (OCCs) strongly decreases hyaluronan (HA) synthesis and its retention in the matrix, as well as progesterone synthesis. Although porcine cumulus cells undergo expansion independently of oocytes, we use biochemical and gene expression analyses to show that they do require activation of SMAD2/3 for optimal stimulation of HA synthesis and proteins involved in the organization of this polymer in the expanded matrix. Furthermore, FSH-induced progesterone synthesis by porcine cumulus cells was increased by blocking SMAD2/3 activation. In conclusion, these results support the hypothesis that an FSH-EGF autocrine loop is active in porcine OCCs, and provide the first evidence that the SMAD2/3 signaling pathway is induced by paracrine/autocrine factors in porcine cumulus cells and is involved in the control of both cumulus expansion and steroidogenesis.
- MeSH
- benzamidy farmakologie MeSH
- C-reaktivní protein metabolismus MeSH
- chinazoliny farmakologie MeSH
- dioxoly farmakologie MeSH
- epidermální růstový faktor metabolismus MeSH
- erbB receptory antagonisté a inhibitory metabolismus MeSH
- folikuly stimulující hormon metabolismus MeSH
- glukuronosyltransferasa antagonisté a inhibitory metabolismus MeSH
- isochinoliny farmakologie MeSH
- kumulární buňky metabolismus MeSH
- kyselina hyaluronová biosyntéza MeSH
- meióza účinky léků MeSH
- molekuly buněčné adheze antagonisté a inhibitory metabolismus MeSH
- myši MeSH
- oocyty enzymologie fyziologie MeSH
- prasata MeSH
- progesteron biosyntéza MeSH
- protein Smad2 antagonisté a inhibitory metabolismus MeSH
- protein Smad3 antagonisté a inhibitory metabolismus MeSH
- pyridiny farmakologie MeSH
- pyrroly farmakologie MeSH
- sérový amyloidový protein metabolismus MeSH
- signální transdukce účinky léků MeSH
- tyrphostiny farmakologie MeSH
- vývojová regulace genové exprese účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
