title: Akap1 Deficiency Promotes Mitochondrial Aberrations and Exacerbates Cardiac Injury Following Permanent Coronary Ligation via Enhanced Mitophagy and Apoptosis.
abstract: A-kinase anchoring proteins (AKAPs) transmit signals cues from seven-transmembrane receptors to specific sub-cellular locations. Mitochondrial AKAPs encoded by the Akap1 gene have been shown to modulate mitochondrial function and reactive oxygen species (ROS) production in the heart. Under conditions of hypoxia, mitochondrial AKAP121 undergoes proteolytic degradation mediated, at least in part, by the E3 ubiquitin ligase Seven In-Absentia Homolog 2 (Siah2). In the present study we hypothesized that Akap1 might be crucial to preserve mitochondrial function and structure, and cardiac responses to myocardial ischemia. To test this, eight-week-old Akap1 knockout mice (Akap1-/-), Siah2 knockout mice (Siah2-/-) or their wild-type (wt) littermates underwent myocardial infarction (MI) by permanent left coronary artery ligation. Age and gender matched mice of either genotype underwent a left thoracotomy without coronary ligation and were used as controls (sham). Twenty-four hours after coronary ligation, Akap1-/- mice displayed larger infarct size compared to Siah2-/- or wt mice. One week after MI, cardiac function and survival were also significantly reduced in Akap1-/- mice, while cardiac fibrosis was significantly increased. Akap1 deletion was associated with remarkable mitochondrial structural abnormalities at electron microscopy, increased ROS production and reduced mitochondrial function after MI. These alterations were associated with enhanced cardiac mitophagy and apoptosis. Autophagy inhibition by 3-methyladenine significantly reduced apoptosis and ameliorated cardiac dysfunction following MI in Akap1-/- mice. These results demonstrate that Akap1 deficiency promotes cardiac mitochondrial aberrations and mitophagy, enhancing infarct size, pathological cardiac remodeling and mortality under ischemic conditions. Thus, mitochondrial AKAPs might represent important players in the development of post-ischemic cardiac remodeling and novel therapeutic targets.
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.|Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Gabriele Giacomo
authors.initials: GG
authors.lastname: Schiattarella
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cattaneo
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.|Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Pironti
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Magliulo
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carotenuto
authors.affiliation: Institute of Protein Biochemistry, Italian National Research Council (CNR-IBP), Naples, Italy.
authors.forename: Marinella
authors.initials: M
authors.lastname: Pirozzi
authors.affiliation: Telethon Institute of Genetic and Medicine (TIGEM), Naples, Italy.
authors.forename: Roman
authors.initials: R
authors.lastname: Polishchuk
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Borzacchiello
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Paolillo
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Oliveti
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Boccella
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Avvedimento
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Sepe
authors.affiliation: Department of Biology, Federico II University, Naples, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Lombardi
authors.affiliation: Department of Biology, Federico II University, Naples, Italy.
authors.forename: Rosa Anna
authors.initials: RA
authors.lastname: Busiello
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Feliciello
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Perrino
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004195:Disease Models, Animal; D004452:Echocardiography; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D063306:Mitophagy / Q000187:drug effects; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; C486333:Akap1 protein, mouse; D017382:Reactive Oxygen Species; C025946:3-methyladenine; C533102:Siah2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000225:Adenine