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Connexin43 cardiac gap junction remodeling: lessons from genetically engineered murine models
Benjamin F Remo1, Steven Giovannone, Glenn I Fishman
1Leon H. Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, NY 10016, USA.
Abstract:
Sudden cardiac death is responsible for several hundred thousand deaths each year in the United States. Multiple lines of evidence suggest that perturbation of gap junction expression and function in the heart, or what has come to be known as cardiac gap junction remodeling, plays a key mechanistic role in the pathophysiology of clinically significant cardiac arrhythmias. Here we review recent studies from our laboratory using genetically engineered murine models to explore mechanisms implicated in pathologic gap junction remodeling and their proarrhythmic consequences, with a particular focus on aberrant posttranslational phosphorylation of connexin43.
Insights
Cardiac gap junction remodeling, particularly connexin43 phosphorylation, is a key factor in sudden cardiac death and arrhythmias. Our research in mouse models explores these mechanisms and their proarrhythmic effects.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Sudden cardiac death causes hundreds of thousands of deaths annually in the US.
- Cardiac gap junction remodeling is implicated in the development of life-threatening cardiac arrhythmias.
- Connexin43 (Cx43) is a critical gap junction protein in the heart.
Purpose of the Study:
- To investigate the mechanisms underlying pathological cardiac gap junction remodeling.
- To explore the proarrhythmic consequences of altered gap junction function.
- To focus on the role of connexin43 posttranslational modifications, specifically phosphorylation.
Main Methods:
- Utilized genetically engineered murine models to study cardiac gap junctions.
- Examined alterations in gap junction expression and function.
- Investigated aberrant posttranslational phosphorylation of connexin43.
Main Results:
- Perturbation of gap junction expression and function contributes to cardiac arrhythmias.
- Aberrant phosphorylation of connexin43 is a key mechanism in pathological remodeling.
- These changes lead to proarrhythmic consequences.
Conclusions:
- Cardiac gap junction remodeling, especially Cx43 phosphorylation, is a significant contributor to sudden cardiac death.
- Understanding these mechanisms in mouse models provides insights into human cardiac arrhythmias.
- Targeting connexin43 phosphorylation may offer therapeutic strategies for preventing arrhythmias.
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