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
Left ventricular hypertrophy (LVH) is due to pressure overload or mechanical stretch and is thought to be associated with remodeling of gap-junctions. We investigated whether the expression of connexin 43 (Cx43) is altered in humans in response to different degrees of LVH. The expression of Cx43 was analyzed by quantitative polymerase chain reaction, Western blot analysis and immunohistochemistry on left ventricular biopsies from patients undergoing aortic or mitral valve replacement. Three groups were analyzed: patients with aortic stenosis with severe LVH (n=9) versus only mild LVH (n=7), and patients with LVH caused by mitral regurgitation (n=5). Cx43 mRNA expression and protein expression were similar in the three groups studied. Furthermore, immunohistochemistry revealed no change in Cx43 distribution. We can conclude that when compared with mild LVH or with LVH due to volume overload, severe LVH due to chronic pressure overload is not accompanied by detectable changes of Cx43 expression or spatial distribution.
- MeSH
- aortální stenóza MeSH
- biopsie MeSH
- financování organizované MeSH
- funkce levé komory srdeční MeSH
- hypertrofie levé komory srdeční MeSH
- imunohistochemie MeSH
- konexin 43 analýza genetika MeSH
- krevní tlak MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA analýza MeSH
- mitrální insuficience MeSH
- myokard chemie patologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- regulace genové exprese MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- western blotting MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
Genetic component represents an important factor in the development of hypertension, which is known to be associated with changes in expression of vascular gap junction protein connexin 43 (Cx43). The aim of the study was to examine the distribution and expression of Cx43 in the aortic endothelium of adult normotensive Wistar rats (W), borderline hypertensive rats (BHR) and spontaneously hypertensive rats (SHR). Rings of the thoracic aorta were processed for immunofluorescence and Western blot analysis of endothelial Cx43 and for electron microscopy. Both, BHR and SHR exhibited significantly increased blood pressure vs. W (132+/-2 mm Hg and 185+/-3 mm Hg vs. 110+/-2 mm Hg). Reduced Cx43 immunofluorescence was observed in the endothelium of BHR and these alterations were more pronounced in SHR. Western blot analysis showed significant suppression of Cx43 expression in the aorta of both BHR (p<0.05) and SHR (p<0.001) vs. W. Electron microscopy revealed local subcellular alterations of interendothelial connections in BHR including extended tight junctions. These alterations were more frequent and marked in SHR. The results indicate that connexin 43 expression is reduced in the aortic endothelium already in prehypertensive period, which may affect cell-to-cell communication and thus participate in acceleration of hypertensive disease.
- MeSH
- aorta thoracica chemie ultrastruktura MeSH
- cévní endotel chemie ultrastruktura MeSH
- down regulace MeSH
- fluorescenční protilátková technika MeSH
- hypertenze metabolismus patologie patofyziologie MeSH
- konexin 43 analýza MeSH
- krevní tlak MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- potkani inbrední SHR MeSH
- potkani Wistar MeSH
- progrese nemoci MeSH
- těsný spoj chemie MeSH
- transmisní elektronová mikroskopie MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- MeSH
- elektronová mikroskopie metody využití MeSH
- finanční podpora výzkumu jako téma MeSH
- fluorescenční protilátková technika metody využití MeSH
- konexin 43 analýza MeSH
- krysa rodu rattus MeSH
- semenný epitel anatomie a histologie cytologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- abstrakt z konference MeSH
