AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Signaling

Background:

• Signaling via the β2-adrenergic receptor is crucial in heart failure, involving cyclic adenosine 3',5'-monophosphate (cAMP) and protein kinase A (PKA).
• Phosphodiesterases (PDEs) regulate cAMP levels, and A kinase anchoring proteins (AKAPs) are potential therapeutic targets.
• AKAP12, expressed in the heart, interacts with β2-adrenergic receptor, PKA, and PDE4D, but its cardiac function role is unknown.

Purpose of the Study:

• To investigate the role of AKAP12 in cardiac function and its association with heart failure.
• To elucidate the molecular mechanisms by which AKAP12 influences cardiac cell signaling.

Main Methods:

• Real-time cAMP detection using a luciferase biosensor in AC16 cells overexpressing AKAP12.
• Assessment of cardiomyocyte contractility and calcium handling in AKAP12-overexpressing mice treated with isoproterenol (ISO).
• Evaluation of cardiac function and left ventricular size in mice after chronic ISO administration and analysis of AKAP12 expression in heart failure patients.

Main Results:

• AKAP12 upregulation reduced intracellular cAMP levels via PDE8 in AC16 cells.
• AKAP12-overexpressing cardiomyocytes showed impaired contractility and calcium handling, reversed by a PDE8 inhibitor.
• AKAP12-overexpressing mice exhibited worsened systolic function and cardiac enlargement; AKAP12 was upregulated in end-stage heart failure patients.

Conclusions:

• AKAP12 upregulation in cardiac tissue contributes to cardiac dysfunction.
• The AKAP12-PDE8 axis is implicated in the accelerated cardiac dysfunction observed in heart failure.