Metoprolol Mitigates Ischemic Heart Remodeling and Fibrosis by Increasing the Expression of AKAP5 in Ischemic Heart.

The harm of heart failure mainly causes patients to develop dyspnea, fatigue, fluid retention, and other symptoms, which impair patients' activity tolerance and lead to a dramatic decrease in patients' quality of life. The purpose of this study was to verify whether metoprolol regulates AKAP5 expression and test the role of AKAP5 postinjury in mitigating cardiac infarction-associated tissue remodeling and fibrosis. Sprague-Dawley (SD) rats underwent coronary artery ligation (CAL), which was followed immediately with metoprolol daily. And western blot and coimmunoprecipitation experiments were performed to detect the expression of related proteins in the sham-operated group, model group, and drug-treated group. HW/BW ratio and cardiac expression of COL1 and COL3 were increased in rats following CAL compared with shams. Treatment with metoprolol postinjury was associated with a decrease in HW/BW ratio and COL1/COL3 expression compared to uncontrolled rats. CAL resulted in decreased cardiac AKAP5 expression compared to the control group, while metoprolol treatment restored levels compared to baseline shams. Cardiac expression levels of NFATc3/p-NFATc3 and GATA4 were modest at baseline and increased with injury, whereas metoprolol suppressed gene expression to below injury-associated changes. Immunoprecipitation indicated that AKAP5 could bind and regulate PP2B. In summary, we know that metoprolol alleviates ischemic cardiac remodeling and fibrosis, and the mechanism of alleviating remodeling may improve cardiac AKAP5 expression and AKAP5-PP2B interaction.

AKAP5 anchors PKA to enhance regulation of the HERG channel.

The activation of the ß-adrenergic receptor (ß-AR) regulates the human ether a-go-go-related gene (HERG) channel via protein kinase A (PKA), which in turn induces lethal arrhythmia in patients with long QT syndromes (LQTS). However, the role of A-kinase anchoring proteins (AKAPs) in PKA's regulation of the HERG channel and its molecular mechanism are not clear. Here, HEK293 cells were transfected with the HERG gene alone or co-transfected with HERG and AKAP5 using Lipofectamine 2000. Western blotting was performed to determine HERG protein expression, and immunofluorescence and immunoprecipitation were used to assess the binding and cellular colocalization of HERG, AKAP5, and PKA. The HEK293-HERG and HEK293-HERG + AKAP5 cells were treated with forskolin at different concentrations and different time. HERG protein expression significantly increased under all treatment conditions (P < 0.001). The level of HERG protein expression in HEK293-HERG + AKAP5 cells was higher than that observed in HEK293-HERG cells (P < 0.001). Immunofluorescence and immunoprecipitation indicated that HERG bound to PKA and AKAP5 and was colocalized at the cell membrane. The HERG channel protein, AKAP5, and PKA interacted with each other and appeared to form intracellular complexes. These results provide evidence for a novel mechanism which AKAP5 anchors PKA to up-regulate the HERG channel protein.