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Cardiac light chain amyloidosis: The role of metal ions in oxidative stress and mitochondrial damage.

著者 Diomede L , Romeo M , Rognoni P , Beeg M , Foray C , Ghibaudi E , Palladini G , Cherny RA , Verga L , Capello GL , Perfetti V , Fiordaliso F , Merlini G , Salmona M
Antioxid Redox Signal.2017 Jan 28 ; ():.
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<b>Aims: </b>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 radical 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 absence of reliable vertebrate model of AL we employed the nematode <i>Caenorhabdistis elegans</i>, whose pharynx is an "ancestral heart". <b>Results:</b> LC purified from patients with severe cardiac involvement intrinsically generated high levels of ROS and, when administered to <i>C. elegans</i> induced ROS production, activation of the DAF-16/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. <b>Innovation and Conclusion</b>: Our findings identify the key role of metal ions in driving the ROS-mediated toxic effects of LC. This is a novel conceptual advance which paves the way for new pharmacological strategies aimed at not only counteracting but totally inhibiting the vicious cycle of redox damage.
PMID: 28132512 [PubMed - as supplied by publisher]
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