Résumé :
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Phospholamban (PLN), the reversible inhibitor of SERCA2, is a key regulator or calcium homeostasis and cardiac function, and it has been directly implicated in the development of dilated cardiomyopathy. Its amino acid sequence is highly conserved across species except for humans where Asn is replaced by Lys at amino acid position 27. To evaluate the significance of this single nucleotide difference we induced cardiac-specific insertion of the human-PLN in the null background. The “humanized” PLN expressing transgenic (TG) mouse hearts presented increased inhibition of SERCA2, abnormal calcium handling, fibrosis, and hypertrophy. Using microarrays, we identified the global molecular pathways implicated in these processes, including ion transport, muscle contraction, cell cycle and proteolysis. The observed changes in key sodium, potassium and calcium plasma membrane pumps were confirmed at the protein level and suggested an ongoing electrical remodeling process with direct implications in cardiac function. In support of this findings, ex vivo Langedorff perfusion of intact hearts further revealed decreased rates of contraction and relaxation in TGs. Furthermore, patch clamp analysis of isolated cardiac myocytes unveiled significant alterations of their electrophysiological properties. Specifically, the cardiac myocyte action potential duration was significantly prolonged, the transient outward current (Ito) was decreased and the sodium/calcium exchanger activity was increased in TG compared to wild-type mice. In conclusion, “human-PLN” directly affects calcium cycling and contractility, which in turn triggers electrical remodeling through differential expression of key ion channels.
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