Loss of Akap1 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Mitochondrial Function

Background:

• Left ventricular hypertrophy (LVH) is a primary driver of heart failure (HF).
• Cyclic adenosine monophosphate (cAMP)-dependent signaling, regulated by A-kinase anchoring proteins (AKAPs), influences cardiomyocyte hypertrophy and mitochondrial dysfunction in LVH and HF.
• MitoAKAPs, encoded by AKAP1, are crucial for mitochondrial PKA localization, impacting mitochondrial health, reactive oxygen species (ROS) production, and cell survival.

Purpose of the Study:

• To investigate the role of mitoAKAPs, specifically AKAP1, in the development of pressure overload-induced LVH and cardiac dysfunction.
• To determine if genetic deletion of AKAP1 exacerbates pathological cardiac remodeling and heart failure progression.

Main Methods:

• Mice with global genetic deletion of AKAP1 (Akap1-/-), heterozygous (Akap1+/-), and wild-type (wt) littermates were subjected to transverse aortic constriction (TAC) or SHAM surgery for one week.
• Cardiac structure, function, cardiomyocyte size, fibrosis, apoptosis, and Akt signaling were assessed.
• Experiments also involved Siah2 knockout mice to examine the role of AKAP121 degradation.

Main Results:

• Pressure overload in wt mice downregulated the cardiac mitoAKAP, AKAP121.
• Akap1-/- mice exhibited exacerbated LVH, cardiomyocyte hypertrophy, and accelerated progression to HF following TAC compared to wt mice.
• Loss of AKAP1 led to increased cardiac apoptosis and impaired Akt signaling activation after pressure overload.
• Preventing AKAP121 degradation in Siah2-/- mice mitigated the exacerbated cardiac remodeling.

Conclusions:

• Genetic deletion of AKAP1 enhances pathological LVH and accelerates pressure overload-induced cardiac dysfunction.
• AKAP1 acts as a novel repressor of pathological LVH, highlighting the critical role of mitoAKAPs in the cardiac stress response.
• Targeting AKAP1 may offer a therapeutic strategy for mitigating adverse cardiac remodeling in response to stress.