Copyright © 2005, European Society of Cardiology
Gap junctional remodeling by hypoxia in cultured neonatal rat ventricular myocytes
aRappaport Faculty of Medicine, Technion, Haifa, Israel
bDepartment of Experimental Cardiology, Max-Planck Institute, Bad Nauheim, Germany
cDepartment of Pharmacology, Columbia University, New York, NY, United States
* Corresponding author. Rappaport Institute, P.O.B 9697, Haifa 31096, Israel. Tel.: +972 4 8295262; fax: +972 4 8513919. Email address: binah{at}tx.technion.ac.il
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% O2) 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.
KEYWORDS Hypoxia; Connexins; Gap junctions; Myocytes; Arrhythmia
1 These authors contributed equally to the manuscript.
Time for primary review 21 days
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