title: Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation.
abstract: Fibrosis following myocardial infarction is associated with increases in arrhythmias and sudden cardiac death. Initial steps in the development of fibrosis are not clear; however, it is likely that cardiac fibroblasts play an important role. In immune cells, ATP release from pannexin 1 (Panx1) channels acts as a paracrine signal initiating activation of innate immunity. ATP has been shown in noncardiac systems to initiate fibroblast activation. Therefore, we propose that ATP release through Panx1 channels and subsequent fibroblast activation in the heart drives the development of fibrosis in the heart following myocardial infarction. We identified for the first time that Panx1 is localized within sarcolemmal membranes of canine cardiac myocytes where it directly interacts with the postsynaptic density 95/Drosophila disk large/zonula occludens-1-containing scaffolding protein synapse-associated protein 97 via its carboxyl terminal domain (amino acids 300-357). Induced ischemia rapidly increased glycosylation of Panx1, resulting in increased trafficking to the plasma membrane as well as increased interaction with synapse-associated protein 97. Cellular stress enhanced ATP release from myocyte Panx1 channels, which, in turn, causes fibroblast transformation to the activated myofibroblast phenotype via activation of the MAPK and p53 pathways, both of which are involved in the development of cardiac fibrosis. ATP release through Panx1 channels in cardiac myocytes during ischemia may be an early paracrine event leading to profibrotic responses to ischemic cardiac injury.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Dolmatova
authors.forename: Gaelle
authors.initials: G
authors.lastname: Spagnol
authors.forename: Daniela
authors.initials: D
authors.lastname: Boassa
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Baum
authors.forename: Kimberly
authors.initials: K
authors.lastname: Keith
authors.forename: Cinzia
authors.initials: C
authors.lastname: Ambrosi
authors.forename: Maria I
authors.initials: MI
authors.lastname: Kontaridis
authors.forename: Paul L
authors.initials: PL
authors.lastname: Sorgen
authors.forename: Gina E
authors.initials: GE
authors.lastname: Sosinsky
authors.forename: Heather S
authors.initials: HS
authors.lastname: Duffy
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D018920:Coculture Techniques; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006031:Glycosylation; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication; D010641:Phenotype; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D021381:Protein Transport; D012508:Sarcolemma / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D000255:Adenosine Triphosphate