TNF alpha Modulates Cardiac Conduction by Altering Electrical Coupling between Myocytes

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dc.contributor.authorGeorge, Sharon A.en
dc.contributor.authorCalhoun, Patrick J.en
dc.contributor.authorGourdie, Robert G.en
dc.contributor.authorSmyth, James W.en
dc.contributor.authorPoelzing, Stevenen
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentBiomedical Engineering and Sciencesen
dc.date.accessioned2019-10-30T13:05:08Zen
dc.date.available2019-10-30T13:05:08Zen
dc.date.issued2017-05-23en
dc.description.abstractBackground: Tumor Necrosis Factor alpha (TNF alpha) upregulation during acute inflammatory response has been associated with numerous cardiac effects including modulating Connexin43 and vascular permeability. This may in turn alter cardiac gap junctional (GJ) coupling and extracellular volume (ephaptic coupling) respectively. We hypothesized that acute exposure to pathophysiological TNF alpha levels can modulate conduction velocity (CV) in the heart by altering electrical coupling: GJ and ephaptic. Methods and Results: Hearts were optically mapped to determine CV from control, TNF alpha and TNF alpha + high calcium(2.5 vs. 1.25 mM) treated guinea pig hearts over 90 mins. Transmission electron microscopy was performed to measure changes in intercellular separation in the gap junction-adjacent extracellular nanodomain-perinexus (W-P). Cx43 expression and phosphorylation were determined by Western blotting and Cx43 distribution by confocal immunofluorescence. At 90 mins, longitudinal and transverse CV (CVL and CVT, respectively) increased with control Tyrode perfusion but TNF alpha slowed CVT alone relative to control and anisotropy of conduction increased, but not significantly. TNF alpha increased W-P relative to control at 90 mins, without significantly changing GJ coupling. Increasing extracellular calcium after 30 mins of just TNF alpha exposure increased CVT within 15 mins. TNF alpha + high calcium also restored CVT at 90 mins and reduced W-P to control values. Interestingly, TNF alpha + high calcium also improved GJ coupling at 90 mins, which along with reduced W-P may have contributed to increasing CV. Conclusions: Elevating extracellular calcium during acute TNF alpha exposure reduces perinexal expansion, increases ephaptic, and GJ coupling, improves CV and may be a novel method for preventing inflammation induced CV slowing.en
dc.description.notesThis work was supported by an R01-HL102298 awarded to SP and R01-HL056728 awarded to RG, a VTCRI Medical Research Scholar Award, an American Heart Association Predoctoral fellowship, and the David W. Francis and Lillian Francis Scholarship Fund awarded to SG.en
dc.description.sponsorshipAmerican Heart Association Predoctoral fellowshipAmerican Heart Association; David W. Francis and Lillian Francis Scholarship Fund; VTCRI Medical Research Scholar Award; [R01-HL102298]; [R01-HL056728]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fphys.2017.00334en
dc.identifier.issn1664-042Xen
dc.identifier.other334en
dc.identifier.pmid28588504en
dc.identifier.urihttp://hdl.handle.net/10919/95214en
dc.identifier.volume8en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectTNF alphaen
dc.subjectconductionen
dc.subjectcalciumen
dc.subjectephaptic couplingen
dc.subjectconnexin43en
dc.titleTNF alpha Modulates Cardiac Conduction by Altering Electrical Coupling between Myocytesen
dc.title.alternativeTNFα Modulates Cardiac Conduction by Altering Electrical Coupling between Myocytesen
dc.title.serialFrontiers in Physiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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