Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Mutations in the type-2 ryanodine receptor ion channel (Ryr2) impair intracellular Ca(2+) handling, leading to cardiac hypertrophy and early death in Ryr2(ADA/ADA) mice.
• Understanding the molecular signaling pathways involved in this cardiac pathology is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the role of signaling molecules, specifically calcineurin/NFAT and Erk/RSK pathways, in the development of cardiac hypertrophy in Ryr2(ADA/ADA) mice.
• To determine if targeting these pathways can ameliorate cardiac dysfunction and improve survival.

Main Methods:

• Monitoring NFAT transcriptional activity using a luciferase reporter transgene.
• Generating and analyzing Ryr2(ADA/ADA) mice with knockout of calcineurin A-β (CNA-β).
• Assessing cardiac function, gene expression, and protein phosphorylation (Akt1, HDAC, MEF2, Erk1/2, p90RSKs, GSK-3β) at different developmental stages.

Main Results:

• NFAT activity was not upregulated early but increased postnatally in Ryr2(ADA/ADA) hearts.
• Ablation of CNA-β extended lifespan and improved cardiac function but did not improve Ca(2+) handling or suppress hypertrophy-related genes.
• Early in development (embryonic day 16.5), Ryr2(ADA/ADA) hearts showed normal weights and Akt1/HDAC/MEF2 activity but increased Erk1/2 and p90RSK phosphorylation, correlating with reduced GSK-3β activity.

Conclusions:

• Impaired calmodulin regulation of RyR2 in early development is not associated with altered CNA-β/NFAT, HDAC/MEF2, or Akt signaling.
• Increased Erk1/2 and p90RSK phosphorylation, leading to reduced GSK-3β activity, precedes cardiac hypertrophy in Ryr2(ADA/ADA) mice.
• These findings highlight a distinct early signaling event in the pathogenesis of ryanodine receptor-associated cardiac hypertrophy.