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 Pannexin1 (Panx1) channels acts as a paracrine signal initiating activation of innate immunity. ATP has been shown in non-cardiac systems to initiate fibroblast activation. Therefore we propose that ATP release through Panx1 channels and subsequent fibroblast activation in the heart drives 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 PDZ-containing scaffolding protein Synapse Associated Protein 97 (SAP97) 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 SAP97. 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 development of cardiac fibrosis. ATP release through Panx1 channels in cardiac myocytes during ischemia may be an early paracrine event leading to pro-fibrotic responses to ischemic cardiac injury.
- Ion Channel
- Myocardial Infarction
- Copyright © 2012, American Journal of Physiology - Heart and Circulatory Physiology