Reversible atrial gap junction remodeling during hypoxia/reoxygenation and ischemia: a possible arrhythmogenic substrate for atrial fibrillation.

Anna Severino, Maria L. Narducci, Daniela Pedicino, Vincenzo Pazzano, Ada F. Giglio, Luigi M. Biasucci, Giovanna Liuzzo, Michela Casella, Stefano Bartoletti, Antonio Dello Russo, Gemma Pelargonio, Pasquale Santangeli, Luigi Di Biase, Andrea Natale, Filippo Crea

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Abstract

Alteration of cardiomyocyte gap-junctions and component connexins (Cx) has been suggested to contribute to the development of atrial fibrillation (AF), including postoperative AF. We tested different possible stimuli, such as hypoxia and ischemia, influencing Cx43 and Cx40 expression and distribution in cultured atrial cells (HL-1) and reversibility of these processes after reoxygenation. Western-blot analysis and immunostaining using anti-Cx43, anti-Cx40 and anti-zonula occludens polyclonal antibodies were performed. HL-1 cells exposed to hypoxia for 24 and 48 h showed a reduction of Cx43 protein levels by 75% and 90% respectively (p < 0.001). During reoxygenation following 24 h of hypoxia, Cx43 levels increased to reach the basal level within 48 h, while they remained at low level during reoxygenation following 48 h of hypoxia. Furthermore, atrial cardiomyocytes subjected to simulated ischemia (SI) were incubated in normoxic and hypoxic conditions for 3, 6, 9, 12 h. Atrial cardiomyocytes subjected to SI in addition to normoxia showed a progressive reduction of Cx43 levels beginning from 3 h. During SI and hypoxia, atrial Cx43 levels showed an initial decrease after 3 h with a subsequent rescue beginning from 6 h of exposure (p = 0.001). Hypoxia and ischemia per se downregulate Cx43 protein expression in atrial cardiomyocytes, but protein downregulation is reversible, depending on hypoxia duration and the association of the two triggers. These alterations characterize several conditions and might contribute to the generation of an arrhythmogenic substrate leading to AF onset and/or maintenance.

Original languageEnglish (US)
Pages (from-to)439-448
Number of pages10
JournalGeneral physiology and biophysics
Volume31
Issue number4
StatePublished - Dec 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Biophysics
  • Physiology

Cite this

Severino, A., Narducci, M. L., Pedicino, D., Pazzano, V., Giglio, A. F., Biasucci, L. M., Liuzzo, G., Casella, M., Bartoletti, S., Dello Russo, A., Pelargonio, G., Santangeli, P., Di Biase, L., Natale, A., & Crea, F. (2012). Reversible atrial gap junction remodeling during hypoxia/reoxygenation and ischemia: a possible arrhythmogenic substrate for atrial fibrillation. General physiology and biophysics, 31(4), 439-448.