Capn4 aggravates angiotensin II-induced cardiac hypertrophy by activating the IGF-AKT signalling pathway

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cell Signaling

Background:

• Calpains are implicated in various biological processes, but the specific role of Capn4 in cardiac disease remains largely unexplored.
• Cardiac hypertrophy, a precursor to heart failure, involves complex molecular signaling pathways.
• Understanding novel regulators of cardiac hypertrophy is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the role of Capn4 in Angiotensin II (Ang II)-induced cardiac hypertrophy.
• To elucidate the molecular mechanisms by which Capn4 influences cardiac hypertrophy, focusing on the IGF-AKT signaling pathway and c-Jun.
• To evaluate Capn4 as a potential therapeutic target for hypertrophic cardiomyopathy.

Main Methods:

• Utilized Angiotensin II (Ang II) treatment in cardiomyocytes and mouse models to induce cardiac hypertrophy.
• Measured Capn4 expression and calpain activity in response to Ang II and a calpain inhibitor (SNJ-1945).
• Employed overexpression and knockdown techniques for Capn4, alongside Western blotting, immunoprecipitation, and ubiquitination assays to assess protein interactions and signaling pathway activation (IGF-AKT, c-Jun).

Main Results:

• Capn4 expression and calpain activity were significantly elevated in Ang II-treated cardiomyocytes and hearts.
• Overexpression of Capn4 exacerbated Ang II-induced cardiac hypertrophy, while Capn4 knockdown attenuated it.
• Capn4 stabilized c-Jun, maintaining IGF-AKT pathway activation, and its silencing partially inhibited c-Jun, reducing hypertrophy.

Conclusions:

• Capn4 plays a critical role in promoting cardiac hypertrophy by enhancing the c-Jun-mediated IGF-AKT signaling pathway.
• Capn4 directly binds and stabilizes c-Jun, preventing its ubiquitination and degradation.
• Capn4 represents a promising therapeutic target for managing hypertrophic cardiomyopathy.