title: Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling.
abstract: BACKGROUND
  Stromal interaction molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiomyocytes. STIM1 is thought to act as an initiator of cardiac hypertrophic response at the level of the sarcolemma, but the pathways underpinning this effect have not been examined.
  
  
  RESULTS
  To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiomyocytes by using in vivo gene delivery of specific short hairpin RNAs. In 3 different models, we found that Stim1 silencing prevents the development of pressure overload-induced hypertrophy but also reverses preestablished cardiac hypertrophy. Reduction in STIM1 expression promoted a rapid transition to heart failure. We further showed that Stim1 silencing resulted in enhanced activity of the antihypertrophic and proapoptotic GSK-3β molecule. Pharmacological inhibition of glycogen synthase kinase-3 was sufficient to reverse the cardiac phenotype observed after Stim1 silencing. At the level of ventricular myocytes, Stim1 silencing or inhibition abrogated the capacity for phosphorylation of Akt(S473), a hydrophobic motif of Akt that is directly phosphorylated by mTOR complex 2. We found that Stim1 silencing directly impaired mTOR complex 2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTOR complex 2.
  
  
  CONCLUSIONS
  These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiomyocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2, which further results in repression of GSK-3β activity.
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Ludovic
authors.initials: L
authors.lastname: Bénard
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Jae Gyun
authors.initials: JG
authors.lastname: Oh
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Marine
authors.initials: M
authors.lastname: Cacheux
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Ahyoung
authors.initials: A
authors.lastname: Lee
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Mathieu
authors.initials: M
authors.lastname: Nonnenmacher
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Matasic
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Erik
authors.initials: E
authors.lastname: Kohlbrenner
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Changwon
authors.initials: C
authors.lastname: Kho
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Catherine
authors.initials: C
authors.lastname: Pavoine
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.). jean.hulot@mssm.edu.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D006332:Cardiomegaly; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000071737:Stromal Interaction Molecule 1; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D015220:Calcium Channels; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; C525637:rictor protein, mouse; C514862:Akt1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3
keywords: Stim1 protein, mouse; TOR complex 2; calcium; genetic therapy; heart failure