AKAP121 downregulation impairs protective cAMP signals, promotes mitochondrial dysfunction, and increases oxidative stress(444 views) Perrino C, Feliciello A, Schiattarella GG, Esposito G, Guerriero R, Zaccaro L, Del Gatto A, Saviano M, Garbi C, Carangi R, Di Lorenzo E, Donato G, Indolfi C, Avvedimento VE, Chiariello M
Cardiovascular Research (ISSN: 0008-6363), 2010 Oct; 88(1): 101-110.
Keywords: Heart Failure, Mitochondria, Oxygen Radicals, Protein Kinase A, Cyclic Amp, Cyclic Amp Dependent Protein Kinase Anchoring Protein, Protein Akap121, Reactive Oxygen Metabolite, Scaffold Protein, Synthetic Peptide, Unclassified Drug, Animal Experiment, Animal Model, Apoptosis, Article, Cell Death, Cell Survival, Disorders Of Mitochondrial Functions, Down Regulation, Heart Left Ventricle Hypertrophy, Heart Muscle Cell, Heart Ventricle Hypertrophy, In Vivo Study, Mitochondrial Membrane, Nonhuman, Oxidative Stress, Priority Journal, A Kinase Anchor Proteins, Newborn, Binding, Competitive, Cultured, Disease Models, Down-Regulation, Left Ventricular, Inbred C57bl, Myocytes, Cardiac, Smooth Muscle, Wistar, Second Messenger Systems,
Affiliations: *** IBB - CNR ***
Division of Cardiology, Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Federico II University, Via Pansini 5, Naples 80131, Italy
Istituto Neurologico Mediterraneo, Pozzilli (IS), Italy
Department of Molecular and Cellular Pathology, Federico II University, Via Pansini 5, Naples 80131, Italy
Istituto di Biostrutture e Bioimmagini (CNR), Naples, Italy
Magna Graecia University, Catanzaro, Italy
The aim of the present study was to determine the function and the role of the scaffold protein AKAP121, tethering cAMP dependent protein kinase A to the outer wall of mitochondria, in neonatal ventricular myocytes and the heart. Competitive peptides displacing AKAP121 from mitochondria in the tissue and in the cells were used to investigate the role of AKAP121 in mitochondrial function, reactive oxygen species (ROS) generation, and cell survival. Displacement of AKAP121 from mitochondria by synthetic peptides triggers the death program in cardiomyocytes. Under pathological conditions in vivo, in a rat model of cardiac hypertrophy induced by ascending aorta banding, the levels of AKAP121 are significantly down-regulated. Disappearance of AKAP121 is associated with mitochondrial dysfunction, high oxidative stress, and apoptosis. In vivo delocalization of AKAP121 by competitive peptides replicates some of the molecular signatures induced by pressure overload: mitochondrial dysfunction, increased mitochondrial ROS, and apoptosis. These data suggest that AKAP121 regulates the response to stress in cardiomyocytes, and therefore AKAP121 downregulation might represent an important event contributing to the development of cardiac dysfunction.