Gap junctional remodeling by hypoxia in cultured neonatal rat ventricular myocytes

Naama Zeevi-Levin, Yaron D. Barac, Yotam Reisner, Irina Reiter, Gal Yaniv, Gideon Meiry, Zaid Abassi, Sawa Kostin, Jutta Schaper, Michael R. Rosen, Nitzan Resnick, Ofer Binah*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: Altered gap junctional coupling of ventricular myocytes plays an important role in arrhythmogenesis in ischemic heart disease. Since hypoxia is a major component of ischemia, we tested the hypothesis that hypoxia causes gap junctional remodeling accompanied by conduction disturbances. Methods: Cultured neonatal rat ventricular myocytes were exposed to hypoxia (1% O 2) for 15 min to 5 h, connexin43 (Cx43) expression was analyzed, and conduction velocity was measured using the Micro-Electrode Array data acquisition system. Results: After 15 min of hypoxia, conduction velocity was unaffected, while total Cx43, including the phosphorylated and nonphosphorylated isoforms, was increased. After 5 h of hypoxia, total Cx43 protein was decreased by 50%, while the nonphosphorylated Cx43 isoform was unchanged. Confocal analyses yielded a 55% decrease in the gap junctional Cx43 fluorescence signal, a 55% decrease in gap junction number, and a 26% decrease in size. The changes in Cx43 were not accompanied by changes in mRNA levels. The reduction in Cx43 protein levels was associated with a ∼20% decrease in conduction velocity compared to normoxic cultures. Conclusions: Short-term hypoxia (5 h) decreases Cx43 protein and conduction velocity, thereby contributing to the generation of an arrhythmogenic substrate.

Original languageEnglish
Pages (from-to)64-73
Number of pages10
JournalCardiovascular Research
Volume66
Issue number1
DOIs
StatePublished - 1 Apr 2005
Externally publishedYes

Funding

FundersFunder number
Bernard Katz Center for Cell Biophysics
US–Israel Binational Foundation
Minerva Foundation
Israel Science Foundation
Max-Planck-Gesellschaft
Ministry of Health, State of Israel

    Keywords

    • Arrhythmia
    • Connexins
    • Gap junctions
    • Hypoxia
    • Myocytes

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