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Gi alpha 1-mediated cardiac electrophysiological remodeling and arrhythmia in hypertrophic cardiomyopathy
Hongmei Ruan1, Scherise Mitchell, Monika Vainoriene
1Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Insights
Cardiac hypertrophy leads to arrhythmias via signaling pathways. Inhibiting G alpha inhibiting subunit 1 (Gi alpha1) reversed electrical remodeling and reduced arrhythmias in a mouse model.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cardiac Electrophysiology
Background:
- Cardiac hypertrophy is a significant risk factor for potentially fatal arrhythmias.
- The precise signaling mechanisms driving arrhythmia induction and electrophysiological remodeling in cardiac hypertrophy remain incompletely understood.
Purpose of the Study:
- To investigate the signaling pathways involved in cardiac hypertrophy and associated arrhythmias.
- To elucidate the role of specific signaling molecules in the electrophysiological remodeling of hypertrophic hearts.
Main Methods:
- Utilized an inducible gene-switch system for temporal and tissue-specific activation of the Ras-Raf-mitogen-activated protein kinases pathway in adult mouse hearts.
- Analyzed electrophysiological properties of isolated ventricular myocytes.
- Performed genome-wide expression profiling to identify differentially expressed genes.
Main Results:
- Ras activation induced ventricular hypertrophy and arrhythmias, temporally correlated with electrophysiological remodeling.
- Observed action potential prolongation, altered ion channel activity, sarcoplasmic reticulum Ca2+ defects, and reduced protein kinase A-dependent phospholamban phosphorylation.
- Discovered selective induction of G alpha inhibiting subunit 1 (Gi alpha1) expression in hypertrophic hearts.
Conclusions:
- Selective induction of Gi alpha1 is a novel downstream event in hypertrophic signaling.
- Gi alpha1 activity appears critical for cellular electrophysiological remodeling and arrhythmia development in hypertrophic cardiomyopathy.
- Pertussis toxin treatment, inhibiting Gi/o proteins, normalized key electrophysiological parameters and reduced arrhythmia frequency.
Background:
Cardiac hypertrophy is a major risk factor for arrhythmias and sudden cardiac death. However, the underlying signaling mechanisms involved in the induction of arrhythmia and electrophysiological remodeling in cardiac hypertrophy are unclear.
Methods And Results:
Using an inducible gene-switch approach, we achieved tissue-specific and temporally regulated induction of a well-established hypertrophic pathway, the Ras-Raf-mitogen-activated protein kinases pathway, in adult mouse heart. On Ras activation, the transgenic animal developed ventricular hypertrophy and arrhythmias. The development of ventricular arrhythmias was temporally correlated with electrophysiological remodeling in isolated ventricular myocytes, including action potential prolongation, increased sodium-calcium exchanger activity, reduced outward potassium currents, sarcoplasmic reticulum Ca2+ defects, and loss of protein kinase A-dependent phospholamban phosphorylation. From genome-wide expression profiling, we discovered a selective induction of G alpha inhibiting subunit 1 (Gi alpha1) expression in the Ras transgenic heart. Treatment of transgenic animals with the Gi/o inhibitor pertussis toxin normalized the phospholamban phosphorylation by protein kinase A, reversed the action potential prolongation, and significantly reduced the frequency of cardiac arrhythmias in Ras transgenic animals.
Conclusions:
These data suggest that selective induction of G alpha inhibiting subunit 1 expression and activity is a novel downstream event in hypertrophic signaling that may be a critical factor leading to cellular electrophysiological remodeling and cardiac arrhythmias in hypertrophic cardiomyopathy.
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