Dynamics of STIM/Orai/TRPC interaction in the normal, hypertrophied and failing cardiac myocyte – Cardiosoc

Ca2+ homeostasis is clearly altered in cardiac hypertrophy and heart failure and new therapeutic approaches for heart failure based on sarcoplasmic reticulum (SR) Ca2+ cycling are under development including viral-based SERCA2a (sarco/endoplasmic reticulum Ca2+ ATPase type 2a) gene transfer. Recently, two new partners of Ca2+ cycling have been described STIM1, a SR/ER Ca2+ sensor and Orai proteins, described as modulators of the non-specific cationic currents through the transient receptor potential cation (TRPC) channels. The dynamics of the STIM1/Orai/TRPC complex has been elegantly studied in non-muscle cells but the dynamics of the endogenous proteins has never been analyzed in cardiac cells. Our objective is to understand how STIM1 and Orai proteins activate Ca2+ influx and the downstream Ca2+-sensitive and cAMP-sensitive signaling pathway in adult cardiac myocytes from normal, hypertrophied and failing hearts. The originality of the study is based on the analysis of endogenously expressed proteins in adult cardiac myocytes. The project is based on a collaboration between two teams that have a common interest on the role of Ca2+ in heart failure but which have different complementary approaches: Partner 1 studies the role of Ca2+ in remodeling using cellular and molecular biology approaches and the role of gene modulation in vivo on cardiac function. In addition,he has developped viral-based vectors to inhibit expression of genes in vivo and in vitro by RNA inteference. Partner 2 uses electrophysiolgy and Ca2+ imaging approaches to study the role of various proteins on cellular physiology and excitation-contraction coupling. Results from this study will give new insights into the mechanism of SR Ca2+ cycling in normal cardiac myocytes and of its implication in cardiac disease. In addition it may open new avenues for therapeutic approaches of heart failure which represents 1% of the population >65 year-old and for whom there is still an unmet need of new therapeutic strategies.