title: Myofibroblasts cause heterogeneous Cx43 reduction and are unlikely to be coupled to myocytes in the healing canine infarct.
abstract: Following myocardial infarction (MI) inflammatory responses transform cardiac fibroblasts to myofibroblasts, which in vitro studies show form heterocellular gap junctions with cardiac myocytes via Connexin43 (Cx43). The ability to form heterocellular junctions in the intact heart and the impact of these junctions on propagation is unclear. We used a canine model of MI and characterized the distribution and quantity of myofibroblasts in surviving epicardial cells [epicardial border zone (EBZ)]. We found a significant increase in myofibroblasts within the EBZ and no gap junction plaques between myofibroblasts and myocytes. Because myofibroblasts produce IL-1β, which downregulates Cx43, we asked whether myofibroblast proliferation causes loss of Cx43 near myofibroblast clusters. In vitro studies showed that IL-1β caused loss of Cx43 and reduced coupling. Western blot showed a significant increase of IL-1β in the EBZ, and immunohistochemistry showed a loss of Cx43 in regions of myofibroblasts in the intact heart. Additionally, dye studies in intact heart showed no coupling between myocytes and myofibroblasts. To quantify the effect of myofibroblasts on propagation we used a two-dimensional subcellular computer model of the EBZ, which showed that heterogeneities in myofibroblast density lead to conduction abnormalities. In conclusion, an increase of myofibroblasts in the infarcted heart causes heterogeneous Cx43 levels, possibly as a result of the release of IL-1β and decreased cell-cell communication, which leads to conduction abnormalities following MI.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Baum
authors.forename: Biao
authors.initials: B
authors.lastname: Long
authors.forename: Candido
authors.initials: C
authors.lastname: Cabo
authors.forename: Heather S
authors.initials: HS
authors.lastname: Duffy
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000502:physiology*; D002460:Cell Line; D003198:Computer Simulation; D018031:Connexin 43 / Q000378:metabolism*; D004285:Dogs; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D017629:Gap Junctions / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism; D007546:Isoquinolines / Q000493:pharmacokinetics; D007668:Kidney / Q000166:cytology; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology; D051381:Rats; D014945:Wound Healing / Q000502:physiology*
chemical_list: D018031:Connexin 43; D005456:Fluorescent Dyes; D053583:Interleukin-1beta; D007546:Isoquinolines; C017475:lucifer yellow
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