AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction

Authors

Hanan Qasim
Mehrdad Rajaei
Ying Xu
Arfaxad Reyes-Alcaraz
Hala Y Abdelnasser
M David Stewart
Satadru K Lahiri
Xander H T Wehrens
Bradley K McConnell

Publication Date

4-12-2024

Journal

Circulation Research

DOI

10.1161/CIRCRESAHA.123.323655

PMID

38506047

PMCID

PMC11075752

PubMedCentral® Posted Date

3-20-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Female, Humans, Male, Mice, 3', 5'-Cyclic-AMP Phosphodiesterases, A Kinase Anchor Proteins, Calcium, Cell Cycle Proteins, Cyclic AMP-Dependent Protein Kinases, Heart Diseases, Heart Failure, Isoproterenol, Myocytes, Cardiac, Receptors, Adrenergic, Up-Regulation, A kinase anchor proteins; calcium; echocardiography; heart; myocytes, cardiac; receptors, adrenergic, beta

Abstract

BACKGROUND: In heart failure, signaling downstream the β2-adrenergic receptor is critical. Sympathetic stimulation of β2-adrenergic receptor alters cAMP (cyclic adenosine 3',5'-monophosphate) and triggers PKA (protein kinase A)-dependent phosphorylation of proteins that regulate cardiac function. cAMP levels are regulated in part by PDEs (phosphodiesterases). Several AKAPs (A kinase anchoring proteins) regulate cardiac function and are proposed as targets for precise pharmacology. AKAP12 is expressed in the heart and has been reported to directly bind β2-adrenergic receptor, PKA, and PDE4D. However, its roles in cardiac function are unclear.

METHODS: cAMP accumulation in real time downstream of the β2-adrenergic receptor was detected for 60 minutes in live cells using the luciferase-based biosensor (GloSensor) in AC16 human-derived cardiomyocyte cell lines overexpressing AKAP12 versus controls. Cardiomyocyte intracellular calcium and contractility were studied in adult primary cardiomyocytes from male and female mice overexpressing cardiac AKAP12 (AKAP12

RESULTS: AKAP12 upregulation significantly reduced total intracellular cAMP levels in AC16 cells through PDE8. Adult primary cardiomyocytes from AKAP12

CONCLUSIONS: AKAP12 upregulation in cardiac tissue is associated with accelerated cardiac dysfunction through the AKAP12-PDE8 axis.

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