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Published on: December 22, 2023
Targeted SERCA2a gene expression identifies molecular mechanism and therapeutic target for arrhythmogenic cardiac
Michael J Cutler1, Xiaoping Wan, Kenneth R Laurita
1The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44109-1998, USA.
Background:
Beat-to-beat alternans of cellular repolarization is closely linked to ventricular arrhythmias in humans. We hypothesized that sarcoplasmic reticulum calcium reuptake by SERCA2a plays a central role in the mechanism of cellular alternans and that increasing SERCA2a gene expression will retard the development of cellular alternans.
Methods And Results:
In vivo gene transfer of a recombinant adenoviral vector with the transgene for SERCA2a (Ad.SERCA2a) was performed in young guinea pigs. Isolated myocytes transduced with Ad.SERCA2a exhibited improved sarcoplasmic reticulum Ca(2+) reuptake (P<0.05) and were markedly resistant to cytosolic calcium alternans (P<0.05) under repetitive constant action potential clamp conditions (ie, when alternation of action potential duration was prevented), proving that sarcoplasmic reticulum Ca(2+) cycling is an important mechanism in the development of cellular alternans. Similarly, SERCA2a overexpression in the intact heart demonstrated significant resistance to alternation of action potential duration when compared with control hearts (heart rate threshold, 484+/-25 bpm versus 396+/-11 bpm, P<0.01), with no change in action potential duration restitution slope. Importantly, SERCA2a overexpression produced a 4-fold reduction in susceptibility to alternans-mediated ventricular arrhythmias (P<0.05).
Conclusions:
These data provide new evidence that sarcoplasmic reticulum Ca(2+) reuptake directly modulates susceptibility to cellular alternans. Moreover, SERCA2a overexpression suppresses cellular alternans, interrupting an important pathway to cardiac fibrillation in the intact heart.
Insights
Increasing sarcoplasmic reticulum calcium reuptake via SERCA2a gene expression significantly reduces cellular alternans and ventricular arrhythmias. This finding highlights SERCA2a
Area of Science:
- Cardiology
- Molecular Biology
- Electrophysiology
Background:
- Beat-to-beat alternans in cellular repolarization are strongly associated with human ventricular arrhythmias.
- The role of sarcoplasmic reticulum calcium reuptake by SERCA2a in cellular alternans remains to be elucidated.
Purpose of the Study:
- To investigate the central role of SERCA2a in the mechanism of cellular alternans.
- To determine if enhanced SERCA2a gene expression can prevent the development of cellular alternans.
Main Methods:
- In vivo gene transfer using an adenoviral vector (Ad.SERCA2a) in guinea pigs.
- Assessment of sarcoplasmic reticulum Ca(2+) reuptake and cytosolic calcium alternans in isolated myocytes.
- Evaluation of action potential duration alternans and arrhythmia susceptibility in intact hearts.
Main Results:
- SERCA2a gene transfer improved sarcoplasmic reticulum Ca(2+) reuptake and conferred resistance to cytosolic calcium alternans.
- Overexpression of SERCA2a in intact hearts increased the threshold for alternans development.
- SERCA2a overexpression led to a significant 4-fold reduction in susceptibility to alternans-mediated ventricular arrhythmias.
Conclusions:
- Sarcoplasmic reticulum Ca(2+) reuptake directly influences susceptibility to cellular alternans.
- SERCA2a overexpression effectively suppresses cellular alternans, mitigating a key pathway to cardiac fibrillation.
