Loss of Exacerbates Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure.

Left ventricular hypertrophy (LVH) is a major contributor to the development of heart failure (HF). Alterations in cyclic adenosine monophosphate (cAMP)-dependent signaling pathways participate in cardiomyocyte hypertrophy and mitochondrial dysfunction occurring in LVH and HF. cAMP signals are received and integrated by a family of cAMP-dependent protein kinase A (PKA) anchor proteins (AKAPs), tethering PKA to discrete cellular locations. AKAPs encoded by the gene (mitoAKAPs) promote PKA mitochondrial targeting, regulating mitochondrial structure and function, reactive oxygen species production, and cell survival. To determine the role of mitoAKAPs in LVH development, in the present investigation, mice with global genetic deletion of (), heterozygous (), and their wild-type () littermates underwent transverse aortic constriction (TAC) or SHAM procedure for 1 week. In mice, pressure overload induced the downregulation of AKAP121, the major cardiac mitoAKAP. Compared to mice did not display basal alterations in cardiac structure or function and cardiomyocyte size or fibrosis. However, loss of exacerbated LVH and cardiomyocyte hypertrophy induced by pressure overload and accelerated the progression toward HF in TAC mice, and these changes were not observed upon prevention of AKAP121 degradation in seven homolog 2 () knockout mice (). Loss of was also associated to a significant increase in cardiac apoptosis as well as lack of activation of Akt signaling after pressure overload. Taken together, these results demonstrate that genetic deletion of enhances LVH development and accelerates pressure overload-induced cardiac dysfunction, pointing at as a novel repressor of pathological LVH. These results confirm and extend the important role of mitoAKAPs in cardiac response to stress.