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Epac2-Rap1 Signaling Regulates Reactive Oxygen Species Production and Susceptibility to Cardiac Arrhythmias
Zhaokang Yang1, Hannah M Kirton1, Moza Al-Owais2
11 Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds , Leeds, United Kingdom .
Aims:
In the heart, β1-adrenergic signaling involves cyclic adenosine monophosphate (cAMP) acting via both protein kinase-A (PKA) and exchange protein directly activated by cAMP (Epac): a guanine nucleotide exchange factor for the small GTPase Rap1. Inhibition of Epac-Rap1 signaling has been proposed as a therapeutic strategy for both cancer and cardiovascular disease. However, previous work suggests that impaired Rap1 signaling may have detrimental effects on cardiac function. The aim of the present study was to investigate the influence of Epac2-Rap1 signaling on the heart using both in vivo and in vitro approaches.
Results:
Inhibition of Epac2 signaling induced early afterdepolarization arrhythmias in ventricular myocytes. The underlying mechanism involved an increase in mitochondrial reactive oxygen species (ROS) and activation of the late sodium current (INalate). Arrhythmias were blocked by inhibition of INalate or the mitochondria-targeted antioxidant, mitoTEMPO. In vivo, inhibition of Epac2 caused ventricular tachycardia, torsades de pointes, and sudden death. The in vitro and in vivo effects of Epac2 inhibition were mimicked by inhibition of geranylgeranyltransferase-1, which blocks interaction of Rap1 with downstream targets.
Innovation:
Our findings show for the first time that Rap1 acts as a negative regulator of mitochondrial ROS production in the heart and that impaired Epac2-Rap1 signaling causes arrhythmias due to ROS-dependent activation of INalate. This has implications for the use of chemotherapeutics that target Epac2-Rap1 signaling. However, selective inhibition of INalate provides a promising strategy to prevent arrhythmias caused by impaired Epac2-Rap1 signaling.
Conclusion:
Epac2-Rap1 signaling attenuates mitochondrial ROS production and reduces myocardial arrhythmia susceptibility. Antioxid. Redox Signal. 27, 117-132.
Insights
Inhibition of Epac2-Rap1 signaling in the heart increases mitochondrial ROS and causes arrhythmias. Blocking the late sodium current (INalate) prevents these detrimental effects, offering a potential therapeutic strategy.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Cellular Signaling
Background:
- Cardiac β1-adrenergic signaling involves cyclic adenosine monophosphate (cAMP) activating protein kinase-A (PKA) and exchange protein directly activated by cAMP (Epac).
- Epac-Rap1 signaling is a target for cancer and cardiovascular disease therapies, but its role in cardiac function requires clarification.
- Previous research suggests potential negative impacts of impaired Rap1 signaling on heart function.
Purpose of the Study:
- To investigate the role of Epac2-Rap1 signaling in cardiac function using in vivo and in vitro models.
- To elucidate the mechanisms by which Epac2-Rap1 signaling influences cardiac electrophysiology and arrhythmogenesis.
- To assess the therapeutic potential of targeting Epac2-Rap1 signaling and related pathways in the heart.
Main Methods:
- Utilized in vitro electrophysiology on ventricular myocytes and in vivo animal models to study Epac2 inhibition.
- Investigated the role of mitochondrial reactive oxygen species (ROS) and the late sodium current (INalate) in Epac2-Rap1 signaling-related arrhythmias.
- Employed geranylgeranyltransferase-1 inhibition to mimic Epac2 inhibition effects by blocking Rap1 interactions.
Main Results:
- Inhibition of Epac2 signaling induced early afterdepolarization arrhythmias in ventricular myocytes via increased mitochondrial ROS and activated INalate.
- Arrhythmias were mitigated by inhibiting INalate or using the antioxidant mitoTEMPO.
- In vivo, Epac2 inhibition led to ventricular tachycardia, torsades de pointes, and sudden death, effects mimicked by geranylgeranyltransferase-1 inhibition.
Conclusions:
- Epac2-Rap1 signaling acts as a negative regulator of mitochondrial ROS production in the heart.
- Impaired Epac2-Rap1 signaling promotes cardiac arrhythmias through ROS-dependent activation of INalate.
- Selective inhibition of INalate presents a promising strategy to prevent arrhythmias associated with Epac2-Rap1 pathway disruption.
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