Akap1 Deficiency Promotes Mitochondrial Aberrations and Exacerbates Cardiac Injury Following Permanent Coronary Ligation via Enhanced Mitophagy and Apoptosis
| Autor: | Rosa Anna Busiello, Marinella Pirozzi, Maria Sepe, Bruno Trimarco, Roberta Paolillo, Giuseppe Carotenuto, Gabriele G. Schiattarella, Marco Oliveti, Assunta Lombardi, Roman S. Polishchuk, Giovanni Esposito, Cinzia Perrino, Fabio Magliulo, Gianluigi Pironti, Fabio Cattaneo, Antonio Feliciello, Domenica Borzacchiello, Nicola Boccella, Marisa Avvedimento |
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| Přispěvatelé: | Schiattarella, GABRIELE GIACOMO, Cattaneo, Fabio, Pironti, Gianluigi, Magliulo, Fabio, Carotenuto, Giuseppe, Pirozzi, Marinella, Polishchuk, Roman, Borzacchiello, Domenica, Paolillo, Roberta, Oliveti, Marco, Boccella, Nicola, Avvedimento, Marisa, Sepe, Maria, Lombardi, Assunta, Busiello, Rosa Anna, Trimarco, Bruno, Esposito, Giovanni, Feliciello, Antonio, Perrino, Cinzia |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology pathogenesi Physiology coronary artery ligation Cardiac fibrosis genotype Myocardial Infarction Mitochondrial Degradation A Kinase Anchor Proteins lcsh:Medicine Apoptosis animal cell thoracotomy Mitochondrion Cardiovascular Physiology Biochemistry Vascular Medicine Mice heart mitochondrion heart infarction size Ischemia Mitophagy Medicine and Health Sciences Myocardial infarction lcsh:Science Energy-Producing Organelles Coronary Arteries disorders of mitochondrial function Mice Knockout Multidisciplinary Cell Death Heart Arteries Mitochondria Echocardiography Cell Processes Knockout mouse Cellular Structures and Organelles Anatomy heart muscle fibrosi Research Article Cardiac function curve autophagy medicine.medical_specialty heart muscle ischemia EMTREE drug terms: 3 methyladenine Ubiquitin-Protein Ligases Autophagic Cell Death Blotting Western animal experiment heart infarction Cardiology Bioenergetics Biology Article animal tissue 03 medical and health sciences Siah2 gene Internal medicine In Situ Nick-End Labeling medicine Animals controlled study gene mouse nonhuman gene deletion Adenine reactive oxygen metabolite EMTREE medical terms: Akap1 gene animal model lcsh:R Correction Biology and Life Sciences Cell Biology medicine.disease apoptosi Disease Models Animal Microscopy Electron mitophagy 030104 developmental biology Endocrinology Cardiovascular and Metabolic Diseases Cardiovascular Anatomy Blood Vessels lcsh:Q cell function Reactive Oxygen Species cell structure |
| Zdroj: | PLoS ONE, Vol 11, Iss 5, p e0154076 (2016) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0154076 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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