title: Cardiac Light Chain Amyloidosis: The Role of Metal Ions in Oxidative Stress and Mitochondrial Damage.
abstract: OBJECTIVE
  The knowledge of the mechanism underlying the cardiac damage in immunoglobulin light chain (LC) amyloidosis (AL) is essential to develop novel therapies and improve patients' outcome. Although an active role of reactive oxygen species (ROS) in LC-induced cardiotoxicity has already been envisaged, the actual mechanisms behind their generation remain elusive. This study was aimed at further dissecting the action of ROS generated by cardiotoxic LC in vivo and investigating whether transition metal ions are involved in this process. In the absence of reliable vertebrate model of AL, we used the nematode Caenorhabditis elegans, whose pharynx is an "ancestral heart."
  
  
  RESULTS
  LC purified from patients with severe cardiac involvement intrinsically generated high levels of ROS and when administered to C. elegans induced ROS production, activation of the DAF-16/forkhead transcription factor (FOXO) pathway, and expression of proteins involved in stress resistance and survival. Profound functional and structural ROS-mediated mitochondrial damage, similar to that observed in amyloid-affected hearts from AL patients, was observed. All these effects were entirely dependent on the presence of metal ions since addition of metal chelator or metal-binding 8-hydroxyquinoline compounds (chelex, PBT2, and clioquinol) permanently blocked the ROS production and prevented the cardiotoxic effects of amyloid LC. Innovation and Conclusion: Our findings identify the key role of metal ions in driving the ROS-mediated toxic effects of LC. This is a novel conceptual advance that paves the way for new pharmacological strategies aimed at not only counteracting but also totally inhibiting the vicious cycle of redox damage. Antioxid. Redox Signal. 27, 567-582.
authors.affiliation: 1 Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri ," Milan, Italy .
authors.forename: Luisa
authors.initials: L
authors.lastname: Diomede
authors.affiliation: 1 Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri ," Milan, Italy .
authors.forename: Margherita
authors.initials: M
authors.lastname: Romeo
authors.affiliation: 2 Amyloid Research and Treatment Center , Foundation IRCCS Policlinico San Matteo, Pavia, Italy .
authors.forename: Paola
authors.initials: P
authors.lastname: Rognoni
authors.affiliation: 1 Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri ," Milan, Italy .
authors.forename: Marten
authors.initials: M
authors.lastname: Beeg
authors.affiliation: 3 Bio-imaging Unit, Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri ," Milan, Italy .
authors.forename: Claudia
authors.initials: C
authors.lastname: Foray
authors.affiliation: 4 Department of Chemistry, University of Turin , Turin, Italy .
authors.forename: Elena
authors.initials: E
authors.lastname: Ghibaudi
authors.affiliation: 2 Amyloid Research and Treatment Center , Foundation IRCCS Policlinico San Matteo, Pavia, Italy .|5 Department of Molecular Medicine, University of Pavia , Pavia, Italy .
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palladini
authors.affiliation: 6 The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Royal Pde, Parkville, Australia .|7 Prana Biotechnology Ltd. , Parkville, Australia .
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
authors.affiliation: 8 Pathologic Unit, Foundation IRCCS Policlinico San Matteo , Pavia, Italy .
authors.forename: Laura
authors.initials: L
authors.lastname: Verga
authors.affiliation: 8 Pathologic Unit, Foundation IRCCS Policlinico San Matteo , Pavia, Italy .
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Capello
authors.affiliation: 9 Medical Oncology Unit, Foundation IRCCS Policlinico San Matteo , Pavia, Italy .
authors.forename: Vittorio
authors.initials: V
authors.lastname: Perfetti
authors.affiliation: 3 Bio-imaging Unit, Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri ," Milan, Italy .
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.affiliation: 2 Amyloid Research and Treatment Center , Foundation IRCCS Policlinico San Matteo, Pavia, Italy .|5 Department of Molecular Medicine, University of Pavia , Pavia, Italy .
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.affiliation: 1 Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri ," Milan, Italy .
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis / Q000378:metabolism*; D008670:Metals / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D015125:Oxyquinoline; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D008670:Metals; D017382:Reactive Oxygen Species; C108831:daf-16 protein, C elegans; D015125:Oxyquinoline
keywords: amyloid; caenorhabditis elegans; immunoglobulin light chain; metals; mitochondria; protein misfolding