The role of A-kinase anchoring proteins in cardiovascular diseases and recent advances

FIGURE 1. AKAP-mediated signaling in cardiomyocyte hypertrophy. The signaling pathways of AKAPs involved in cardiomyocyte hypertrophy, including the AKAP1/5/mAKAP/CaN/NFATc3, AKAP5/PKA/PLN, mAKAP/PLCε/PKD, mAKAP/PKA/PDE4D3, and Gα12/AKAP–Lbc/RhoA/PKD pathways, promote cardiomyocyte hypertrophy upon activation.

FIGURE 2. AKAP signaling in cardiomyocyte apoptosis. The signaling pathways involving AKAPs are crucial for cardiomyocyte apoptosis. Key pathways include AKAP5/PKA/PLN/RyR2, AKAP5/PKC/p47(phox), AKAP1/NDUFS1/OXPHOS, AKAP1/PKA/BAD, AKAP1/PKA/Drp1/Fis1, AKAP1/PTPD1/src, AKAP-Lbc/PKD1/SSH1L/Cofilin2, and AKAP-Lbc/PKD1/Bcl-2. Activation of these pathways promotes cardiomyocyte apoptosis.

FIGURE 3. The role of AKAPs in signaling pathways during cardiac arrhythmias. The AKAP9/AC/PDE4D3/PKA and AKAP9/PP1 complexes regulate KCNQ1 phosphorylation, thus controlling the activity and current kinetics of IKs. Mutations in KCNQ1 within this complex are associated with LQT1. AKAP5 enhances calcium influx, prolongs action potential duration, and promotes arrhythmogenesis by increasing the coupling and gating of the CaV1.2–LQT8 channel, while AKAP5 ablation corrects the CaV1.2–LQT8-related arrhythmias. AKAP10 mutations can result in sinus arrhythmia, sinus arrest, and atrioventricular conduction blocks.

FIGURE 4. Role of AKAP signaling in heart failure. The AKAP signaling pathways involved in heart failure, including the AKAP1/Akt/AS160, AKAP1/PKA/Drp1/Fis1, AKAP1/NDUFS1/OXPHOS, AKAP5/CaN/NFATc3, AKAP5/CaMKII/HDAC, AKAP-Lbc/PKD/HDAC, and mAKAPβ/PLCε/PKD pathways, contribute to heart failure progression through their activation.

FIGURE 5. The role of AKAPs in regulating myocardial contraction and relaxation. The role of AKAPs in regulating myocardial contraction and relaxation is pivotal. Specifically, AKAP5, AKAP18, and mAKAPβ regulate cellular calcium cycling, cardiac contraction, and relaxation by forming complexes with PKA, CaV1.2, PLN, and RyR2. In the absence of AKAPs, disruptions in calcium cycling occur within cardiomyocytes, leading to abnormalities in myocardial contraction and relaxation. Furthermore, mAKAPβ plays a crucial role by interacting with NCX1, thereby promoting PKA-dependent activation of NCX1. This interaction facilitates the efflux of Ca2+, thus influencing myocardial contraction and relaxation.

FIGURE 6. The role of AKAPs in blood pressure regulation. AKAP5 facilitates calcium influx by anchoring PKC to phosphorylate Cav1.2 channels, which activates the CaN/NFATc3 complex. This reduces the expression of the β1 subunit of BKCa, inhibiting potassium efflux, promoting vascular contraction, and raising blood pressure. Additionally, studies show that the AKAP5–PKC complex interacts with the TRPV4 calcium channel, promoting RyRs–BKCa coupling and activating the BKCa channel, thereby suppressing blood pressure elevation.