Cardiac remodeling pathways do not accelerate disease onset and severity in a mouse model of PLN-R14del...

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Disease Modeling

Background:

• Phospholamban (PLN)-R14del is a pathogenic variant linked to ventricular arrhythmias and dilated cardiomyopathy.
• Disease onset and severity in PLN-R14del carriers show high heterogeneity, suggesting other factors influence progression.

Purpose of the Study:

• To investigate if cardiac pressure overload, induced by transverse aortic constriction (TAC), accelerates disease onset in a heterozygous PLN-R14del mouse model (R14Δ/+) .

Main Methods:

• A heterozygous PLN-R14del mouse model (R14Δ/+) underwent TAC surgery to induce pressure overload.
• Wild-type littermates and sham-operated controls were used for comparison.
• Cardiac structure, function, gene expression, and sarco-endoplasmic reticulum integrity were assessed post-surgery.

Main Results:

• TAC induced cardiac remodeling (increased wall thickness, ventricular/atrial weights, reduced ejection fraction) in both R14Δ/+ and wild-type mice.
• Gene expression analysis revealed comparable activation of cardiac remodeling and stress pathways in both groups.
• Importantly, TAC did not induce sarco-endoplasmic reticulum malformation in R14Δ/+ mice, indicating PLN-R14del-specific pathology was not triggered.

Conclusions:

• Transverse aortic constriction provokes significant cardiac remodeling and activates common stress pathways in young adult mice, irrespective of PLN-R14del genotype.
• Pressure overload alone is insufficient to trigger PLN-R14del-specific sarco-endoplasmic reticulum malformation or accelerate disease progression in this model.
• These findings suggest that common cardiac stress pathways are not the sole drivers for accelerating PLN-R14del cardiomyopathy in early adulthood.