AKAP6β-a conductor in the orchestra of pathological cardiomyocyte gene transcription

Heart failure is a major cause of morbidity and mortality worldwide, representing the end stage of cardiovascular diseases that induce pathological cardiac remodeling. At the cellular level, pathological remodeling includes myocyte hypertrophy and decreased survival, changes in myocyte metabolism and contractility, and interstitial myocardial fibrosis, all of which are controlled by a complex network of intracellular signaling pathways. At the outer nuclear envelope of the cardiomyocyte, A-kinase anchoring protein (AKAP) 6β (also known as mAKAPβ) organizes multimolecular signaling complexes called "signalosomes," which include over 25 different signaling enzymes and effector proteins that, in response to cAMP, calcium, and phosphoinositide second messengers, regulate gene expression. The AKAP6β scaffold also binds other scaffold proteins such as AKAP9, permitting higher-order interactions between signaling molecules at the nuclear envelope and adjacent Golgi apparatus. Together, these protein complexes present novel opportunities for compartmentalized inhibition of pathophysiological cardiac remodeling. Both basic molecular mechanisms and potential therapeutic approaches are considered, because this review highlights recent advances in the role of AKAP6 in coordinating compartmentalized signaling and the regulation of cardiomyocyte gene expression promoting heart failure. SIGNIFICANCE STATEMENT: Heart failure is a syndrome of major public health significance. Novel therapies for the treatment of cardiac disease are needed to improve patient quality of life, reduce symptoms, and manage comorbidities associated with heart disease. The A-kinase anchoring protein 6β signalosome has been shown to orchestrate multiple pathological signaling pathways in the cardiomyocyte that induce cardiac disease. Targeting this signalosome should comprise more specific therapeutics for heart failure with fewer side effects than those associated with current treatments.