IL-6/STAT3 signaling in mice with dysfunctional type-2 ryanodine receptor

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Signal Transduction

Background:

• Genetic modification of cardiac ryanodine receptor (Ryr2) leads to impaired calmodulin regulation, severe cardiac hypertrophy, and early mortality in mice.
• The interleukin-6 (IL-6)/signal transducer and activator of transcription-3 (STAT3) signaling pathway is investigated for its role in the cardiac hypertrophy observed in Ryr2 (ADA/ADA) mice.

Purpose of the Study:

• To determine the role of the IL-6/STAT3 signaling pathway in the cardiac hypertrophy and mortality of Ryr2 (ADA/ADA) mice.
• To evaluate the therapeutic potential of targeting STAT3 signaling in this cardiac disease model.

Main Methods:

• Comparison of cardiac function and protein levels (IL-6, pSTAT3-Tyr705/STAT3, c-Fos, c-Myc) in wild-type and Ryr2 (ADA/ADA) mice.
• Assessment of Ryr2 (ADA/ADA) mice with disrupted IL-6 genes and treatment with STAT3 inhibitor NSC74859.
• Analysis of protein localization in nuclear fractions.

Main Results:

• Ryr2 (ADA/ADA) mice showed increased IL-6 at postnatal day 1, and increased pSTAT3-Tyr705/STAT3, c-Fos, and c-Myc at postnatal day 10.
• Nuclear accumulation of STAT3 and pSTAT3-Tyr705 was observed in Ryr2 (ADA/ADA) hearts.
• Deletion of IL-6 or inhibition of STAT3 prolonged lifespan, reduced cardiac hypertrophy, and decreased downstream target protein levels.

Conclusions:

• Upregulation of IL-6 and STAT3 signaling significantly contributes to cardiac hypertrophy and premature death in mice with dysfunctional ryanodine receptors.
• STAT3 inhibitors demonstrate potential as therapeutic agents for conditions involving altered cardiac calcium handling.