AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction
Background: In heart failure, signaling through the β2-adrenergic receptor plays a crucial role in regulating cardiac function. Sympathetic stimulation of this receptor alters cAMP (cyclic adenosine 3′,5′-monophosphate) levels, triggering PKA (protein kinase A)-dependent phosphorylation of proteins involved in heart function. cAMP levels are partially regulated by phosphodiesterases (PDEs). A kinase anchoring proteins (AKAPs), which modulate PKA signaling, are implicated in cardiac function and are emerging as potential therapeutic targets. AKAP12, specifically expressed in the heart, has been shown to directly interact with the β2-adrenergic receptor, PKA, and PDE4D, but its role in cardiac function remains unclear.
Methods: Real-time cAMP accumulation downstream of the β2-adrenergic receptor was monitored for 60 minutes in live AC16 human-derived cardiomyocyte cell lines overexpressing AKAP12 compared to controls using a luciferase-based biosensor (GloSensor). Cardiomyocyte intracellular calcium and contractility were assessed in adult primary cardiomyocytes from male and female mice overexpressing cardiac AKAP12 (AKAP12OX) and wild-type littermates after acute treatment with 100 nM isoproterenol (ISO). Systolic cardiac function was evaluated in mice following 14 days of subcutaneous ISO administration (60 mg/kg per day). Gene and protein expression levels of AKAP12 were measured in left ventricular samples from patients with end-stage heart failure.
Results: Upregulation of AKAP12 in AC16 cells significantly reduced total intracellular cAMP levels through PDE8. In adult primary cardiomyocytes from AKAP12OX mice, ISO-induced contractility and calcium handling were significantly impaired, effects that were reversed with the selective PDE8 inhibitor PF-04957325. AKAP12OX mice exhibited worsened systolic cardiac function and enlarged left ventricles. Furthermore, patients with end-stage heart failure demonstrated increased gene and protein levels of AKAP12 in their left ventricles.
Conclusions: Upregulation of AKAP12 in cardiac tissue is linked to accelerated cardiac dysfunction through the AKAP12-PDE8 axis, suggesting its potential as a target for therapeutic intervention in heart failure.