Transcript Genesis of Cardiac Arrhythmias

Genesis of Cardiac Arrhythmias
Mike Hansen
Biology Department
Eastern CT State University
Role of sodium channel deglycosylation in
the genesis of cardiac arrhythmias
The Journal of Biological Chemistry Vol. 276,
pp. 28,197-28,2003
C. A. Ufret-Vincenty, D. J. Baro, W. J. Lederer, H. A.
Rockman, L. E. Quinones, and L. F. Santana
University of Puerto Rico, University of Maryland School of
Medicine, and Duke University Medical Center
Cardiac arrhythmias
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Leading cause of death in patients with HF
Contractile dysfunction
Possibly due to prolonged AP:
Change in ion currents and Ca+ signaling
Is it deglycosylation?
Methods
• Used a mouse as a
model for HF
• It lacked expression of
MLP
• Compared with
normal heart
Ventricular myocytes
•ECG measurements
•Single cell a.p.
Ion channels
•Ion channels in cell
membrane
•Receive signal to open
•Influx of sodium ions
Action potential
Results
•ECG: longer QT intervals in
MLP than WT (control)
•Shows MLP is abnormal
•AP of MLP and WT
•Reveals a.p. were
longer in MLP
Sodium channels
• Current-voltage
relationship for
sodium channels
• MLP
• WT
•Indicates lower Na channel density in MLP
Voltage dependence for Na
channel inactivation
• Slowing of
inactivation of
channels in MLP
• How are theses
changes produced?
• Changes sufficient
enough to produce a.p.
changes?
Expression of Na channels
•Western blot
•Electrophoresis
• alpha subunit of channel
• reduction in band in
MLP relative to WT
• due to heavy glycosylation
•MLP less glycosylated
Lack of Deglycosylation?
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MLP and WT exposed to neuroaminadase
Reduces extracellular glycosylation
Results on WT were similar to that of HF
Glycosylation alters channels in HF
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Conclusion
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Altered a.p. play a role in arrhythmias
Likely due to glycosylation of Na channels
Neuroamindase effects on WT
Good for mice, what about humans?
?