Interaction between A-kinase anchoring protein 5 and protein kinase A mediates CaMKII/HDAC signaling to inhibit cardiomyocyte hypertrophy after hypoxic reoxygenation

Abstract

We reported that A-kinase anchoring protein 5 (AKAP5) played a role in cardiomyocyte apoptosis after hypoxia-reoxygenation (H/R). The role of AKAP5 in cardiomyocyte hypertrophy has not been fully elucidated. Herein we investigated whether AKAP5 regulates cardiomyocyte hypertrophy through calcium/calmodulin-dependent protein kinase II (CaMKII). After H/R, deficiency of AKAP5 in H9C2 cardiomyocytes and neonatal rat cardiac myocytes activated CaMKII and stimulated cardiomyocyte hypertrophy. AKAP5 upregulation limited this. Low expression of AKAP5 increased CaMKII interaction with histone deacetylases 4/5 (HDAC4/5) and increased nuclear export of HDAC4/5. In addition, AKAP5 interactions with protein kinase A (PKA) and phospholamban (PLN) were diminished. Moreover, the phosphorylation of PLN was decreased, and intracellular calcium increased. Interference of this process with St-Ht31 increased CaMKII signaling, decreased PLN phosphorylation and promoted post-H/R cell hypertrophy. And PKA-anchoring deficient AKAP5ΔPKA could not attenuate hypoxia-reoxygenation-induced cardiomyocyte hypertrophy, but AKAP5 could. Altogether, AKAP5 downregulation exacerbated H/R-induced hypertrophy in cardiomyocytes. This was due to, in part, to less in AKAP5-PKA interaction and the accumulation of intracellular Ca2+ with a subsequent increase in CaMKII activity.