AKAP150 mobilizes cPKC-dependent cardiac glucotoxicity

Area of Science:

• Cardiovascular Biology
• Molecular Signaling
• Metabolic Disease

Background:

• Hyperglycemia-induced cardiac toxicity involves conventional protein kinase C (cPKC) signaling.
• The role of A-kinase anchoring protein 150 (AKAP150) in anchoring and regulating cardiac cPKC signaling is not well-defined.
• Understanding AKAP150's function is crucial for addressing diabetic cardiomyopathy.

Purpose of the Study:

• To investigate the role of AKAP150 in cPKC-mediated cardiac glucotoxicity.
• To elucidate the molecular mechanisms by which AKAP150 contributes to hyperglycemia-induced cardiac damage.

Main Methods:

• Utilized streptozotocin-induced diabetic rat models and high-glucose-treated neonatal rat cardiomyocytes.
• Employed AKAP150 knockdown via adenovirus-mediated shRNA (in vivo and in vitro).
• Assessed cardiac function, cardiomyocyte apoptosis, oxidative stress markers, and protein signaling pathways (cPKC, p65 NF-κB, p47(phox)).
• Utilized immunofluorescence and immunoprecipitation to study AKAP150-cPKC interactions.

Main Results:

• Hyperglycemia significantly increased cardiac AKAP150, cPKC activity, and p65 NF-κB/p47(phox) phosphorylation.
• AKAP150 knockdown reversed diabetes-induced diastolic dysfunction, cardiomyocyte apoptosis, and oxidative stress.
• Reduced AKAP150 inhibited high-glucose-induced cPKC activation and downstream signaling.
• AKAP150 enhanced anchoring and colocalization with PKCα/β isoforms within the plasma membrane under hyperglycemia.

Conclusions:

• Cardiac AKAP150 is upregulated by hyperglycemia and promotes glucotoxicity.
• AKAP150 facilitates cardiac dysfunction, apoptosis, and oxidative stress via a cPKC/p47(phox)/ROS pathway.
• Targeting AKAP150 may offer a therapeutic strategy for diabetic cardiomyopathy.