Critical Role for Stromal Interaction Molecule 1 in Cardiac Hypertrophy

• Published in: Circulation (New York, N.Y.) Vol. 124; no. 7; pp. 796 - 805
• Main Authors: HULOT, Jean-Sébastien, FAUCONNIER, Jeremy, HADRI, Lahouaria, JEONG, Dongtak, MÜHLSTEDT, Silke, SCHMITT, Joachim, BRAUN, Attila, BENARD, Ludovic, SALIBA, Youakim, LAGGERBAUER, Bernhard, NIESWANDT, Bernhard, LACAMPAGNE, Alain, RAMANUJAM, Deepak, HAJJAR, Roger J, LOMPRE, Anne-Marie, ENGELHARDT, Stefan, CHAANINE, Antoine, AUBART, Fleur, SASSI, Yassine, MERKLE, Sabine, CAZORLA, Olivier, OUILLE, Aude, DUPUIS, Morgan
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 16.08.2011; American Heart Association
• Subjects: Adenoviridae - genetics; Age Factors; Animals; Animals, Newborn; Biological and medical sciences; Blood and lymphatic vessels; Caffeine - pharmacology; Calcium - metabolism; Calcium Channels; Calcium Signaling - drug effects; Calcium Signaling - physiology; Cardiology and cardiovascular system; Cardiology. Vascular system; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cardiovascular system; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enzyme Inhibitors - pharmacology; Gene Silencing; Gene Transfer Techniques; Human health and pathology; Life Sciences; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Mice; Mice, Transgenic; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - pathology; Myocytes, Cardiac - physiology; Patch-Clamp Techniques; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - pharmacology; Rats; Santé publique et épidémiologie; Sarcolemma - metabolism; Stromal Interaction Molecule 1; Thapsigargin - pharmacology; Vasodilator agents. Cerebral vasodilators; Human; Calcium; hypertrophy; STIM1 protein; Cardiovascular disease; Gene therapy; Inorganic element; myocytes; Myocyte; cardiac
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.111.031229

Cardiomyocytes use Ca2+ not only in excitation-contraction coupling but also as a signaling molecule promoting, for example, cardiac hypertrophy. It is largely unclear how Ca2+ triggers signaling in cardiomyocytes in the presence of the rapid and large Ca2+ fluctuations that occur during excitation-contraction coupling. A potential route is store-operated Ca2+ entry, a drug-inducible mechanism for Ca2+ signaling that requires stromal interaction molecule 1 (STIM1). Store-operated Ca2+ entry can also be induced in cardiomyocytes, which prompted us to study STIM1-dependent Ca2+ entry with respect to cardiac hypertrophy in vitro and in vivo. Consistent with earlier reports, we found drug-inducible store-operated Ca2+ entry in neonatal rat cardiomyocytes, which was dependent on STIM1. Although this STIM1-dependent, drug-inducible store-operated Ca2+ entry was only marginal in adult cardiomyocytes isolated from control hearts, it increased significantly in cardiomyocytes isolated from adult rats that had developed compensated cardiac hypertrophy after abdominal aortic banding. Moreover, we detected an inwardly rectifying current in hypertrophic cardiomyocytes that occurs under native conditions (i.e., in the absence of drug-induced store depletion) and is dependent on STIM1. By manipulating its expression, we found STIM1 to be both sufficient and necessary for cardiomyocyte hypertrophy in vitro and in the adult heart in vivo. Stim1 silencing by adeno-associated viruses of serotype 9-mediated gene transfer protected rats from pressure overload-induced cardiac hypertrophy. By controlling a previously unrecognized sarcolemmal current, STIM1 promotes cardiac hypertrophy.