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Function of the CaMKII-ryanodine receptor signaling pathway in rabbits with left ventricular hypertrophy and
Jun Ke1, Xing Xiao2, Feng Chen1
1Department of Emergency Internal Medicine, Fujian Provincial Hospital, Provincial Clinical Medical College of Fujian Medical University, Fuzhou 350001, China.
Background:
Calcium calmodulin-dependent kinase II (CaMKII) can be more active in patients with left ventricular hypertrophy (LVH), which in turn causes phosphorylation of ryanodine receptors, resulting in inactivation and the instability of intracellular calcium homeostasis. The present study aimed to determine the effect of CaMKII-ryanodine receptor pathway signaling in rabbits with left ventricular hypertrophy and triggered ventricular arrhythmia.
Methods:
Forty New Zealand rabbits were randomized into four groups (10 per group): sham group, LVH group, KN-93 group (LVH+KN-93), and ryanodine group (LVH+ryanodine). Rabbits in the LVH, KN-93, and ryanodine groups were used to establish a left ventricular hypertrophy model by the coarctation of the abdominal aorta, while those in the sham group did not undergo the coarctation. After eight weeks, action potentials (APs) were recorded simultaneously in the endocardium and epicardium, and a transmural electrocardiogram (ECG) was also recorded in the rabbit left ventricular wedge model. Drugs were administered to the animals in the KN-93 and ryanodine groups, and the frequency of triggered APs and ventricular tachycardia was recorded after the rabbits were given isoprenaline (1 μmol/L) and high-frequency stimulation.
Results:
The frequency (animals/group) of triggered APs was 0/10 in the sham group, 10/10 in the LVH group, 4/10 in the KN-93 group, and 1/10 in the ryanodine group. The frequencies of ventricular tachycardia were 0/10, 9/10, 3/10, and 1/10, respectively. The frequencies of polymorphic ventricular tachycardia or ventricular fibrillation were 0/10, 7/10, 2/10, and 1/10, respectively. The frequencies of triggered ventricular arrhythmias in the KN-93 and ryanodine groups were much lower than those in the LVH group (P<0.05).
Conclusions:
KN-93 and ryanodine can effectively reduce the occurrence of triggered ventricular arrhythmia in rabbits with LVH. The CaMKII-ryanodine signaling pathway can be used as a new means of treating ventricular arrhythmia.
Insights
Calcium calmodulin-dependent kinase II (CaMKII) inhibition and ryanodine treatment significantly reduced triggered ventricular arrhythmias in rabbits with left ventricular hypertrophy (LVH). Targeting the CaMKII-ryanodine pathway offers a novel therapeutic strategy for ventricular arrhythmias.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Left ventricular hypertrophy (LVH) is associated with increased Calcium calmodulin-dependent kinase II (CaMKII) activity.
- CaMKII activation phosphorylates ryanodine receptors, disrupting intracellular calcium homeostasis and potentially leading to arrhythmias.
- The CaMKII-ryanodine receptor pathway's role in LVH-induced triggered ventricular arrhythmias requires further investigation.
Purpose of the Study:
- To investigate the effect of the CaMKII-ryanodine receptor signaling pathway on triggered ventricular arrhythmias in a rabbit model of LVH.
- To evaluate the therapeutic potential of inhibiting CaMKII and targeting ryanodine receptors in preventing these arrhythmias.
Main Methods:
- A rabbit model of LVH was established via abdominal aortic coarctation.
- Rabbits were randomized into sham, LVH, LVH+KN-93 (CaMKII inhibitor), and LVH+ryanodine groups.
- Action potentials and ECGs were recorded, and triggered ventricular arrhythmias were induced and quantified after isoprenaline stimulation.
Main Results:
- LVH rabbits exhibited significantly higher frequencies of triggered action potentials, ventricular tachycardia, and polymorphic ventricular tachycardia/ventricular fibrillation compared to sham controls.
- Treatment with KN-93 or ryanodine markedly reduced the incidence of these triggered ventricular arrhythmias in LVH rabbits (P<0.05).
Conclusions:
- Inhibition of CaMKII with KN-93 and ryanodine administration effectively suppress triggered ventricular arrhythmias in LVH.
- The CaMKII-ryanodine signaling pathway represents a promising therapeutic target for managing ventricular arrhythmias associated with LVH.
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