Abstract 18313: Desmosomal Remodeling Accompanies Connexin43 Lateralization Consequent to Right Ventricular Pressure Overload
It is well accepted that gap junction formation requires the presence of mechanical junctions. Yet, while connexin 43 (Cx43) lateralization in hearts subjected to pressure overload has been studied, the fate of desmosomal proteins under those conditions remains unknown. Here, we use an animal model of right ventricular pressure overload in sheep to characterize the morphology of intercellular junctions formed outside the intercalated disc (ID). Sephadex beads were injected in the pulmonary circulation of 52–65kg sheep every other day for 60 days. Hearts with the clinical diagnosis of pulmonary hypertension (PH) were harvested, fixed for immunochemistry or used for cell isolation. The following proteins were tested: Cx43, plakoglobin, plakophilin-2, desmocollin, desmoplakin and N-cadherin. In control, all signals were found perpendicular to the long axis of the cells, at the ID. However, in right ventricular tissue from PH sheep, signals for desmosomal and gap junction proteins oriented parallel to the long axis. These results indicate loss of junctional complexes at the ID and their neo-formation at the lateral membranes. Little lateralization of N-cadherin was observed, indicating dissociation of desmosomal molecules from adherens junctions, with the latter staying at the myocytes' end. NaV1.5-immunoreactive signals were clearly visible at the ID in control tissue, but rarely discernable from background levels in the right ventricle of PH animals, suggesting that, while desmosomal and gap junction molecules ”abandon” the ID to form complexes in exile, NaV1.5 does not follow. Patch clamp data showed high junctional conductance between myocytes paired side-to-side (81.8 ± 6.5 nS, n=10) indicative of functionality of lateralized gap junctions. We demonstrate for the first time that neo-formation of desmosomes accompanies Cx43 lateralization. These results emphasize the importance of desmosome biology on cardiac electrical function. We propose that desmosomal remodeling is an adaptive event that supports gap junction formation and helps preserve electrical synchrony. Yet, disruption of desmosomal integrity may set the stage for failure of electrical communication, cardiac arrhythmias and increased likelihood of sudden death.
- © 2010 by American Heart Association, Inc.