Critical role for stromal interaction molecule 1 in cardiac hypertrophy

Background-: Cardiomyocytes use Ca not only in excitation-contraction coupling but also as a signaling molecule promoting, for example, cardiac hypertrophy. It is largely unclear how Ca triggers signaling in cardiomyocytes in the presence of the rapid and large Ca fluctuations that occur during excitation-contraction coupling. A potential route is store-operated Ca entry, a drug-inducible mechanism for Ca signaling that requires stromal interaction molecule 1 (STIM1). Store-operated Ca entry can also be induced in cardiomyocytes, which prompted us to study STIM1-dependent Ca entry with respect to cardiac hypertrophy in vitro and in vivo. Methods and results-: Consistent with earlier reports, we found drug-inducible store-operated Ca entry in neonatal rat cardiomyocytes, which was dependent on STIM1. Although this STIM1-dependent, drug-inducible store-operated Ca 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 (ie, 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. Conclusion-: By controlling a previously unrecognized sarcolemmal current, STIM1 promotes cardiac hypertrophy.