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A critical role for STIM1 in cardiac hypertrophy


Jean-Sébastien Hulot Jean-Sebastien Hulot (France)

Presentation slides

List of Authors:
Jean-Sébastien Hulot, Jérémy Fauconnier, Deepak Ramanujam, Antoine Chaanine, Fleur Aubart, Yassine Sassi, Alain Lacampagne, Roger J. Hajjar, Anne-Marie Lompré, Stefan Engelhardt


Background: Cardiomyocytes (CM) use Ca2+ not only in excitation-contraction coupling (ECC) but also as a signaling molecule promoting, for example, cardiac hypertrophy. It is largely unclear how Ca2+ triggers signaling in CM in the presence of the rapid and large Ca2+ fluctuations that occur during ECC. A potential route is store-operated Ca2+ entry (SOCE), a drug-inducible mechanism for Ca2+ signaling that requires stromal interaction molecule 1 (STIM1). SOCE 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.

Methods & results: Consistent with earlier reports, we found drug-inducible SOCE in neonatal rat cardiomyocytes, which was dependent on STIM1. While this STIM1-dependent, drug-inducible SOCE was only marginal in adult cardiomyocytes isolated from control hearts, it significantly increased 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 in isolated neonatal rat cardiomyocytes, STIM1 was found to be both sufficient and necessary for cardiomyocyte hypertrophy and NFAT activation. To deliver RNA interference in vivo, dimeric cardiotropic adeno‐associated virus vectors encoding for a short hairpin RNA against STIM1 or Luciferase (rAAV9‐shSTIM1 or rAAV9‐shLuc) were constructed and administered to Sprague dawley male rats (5x10e11 viral genomes by tail vein injection) 4 weeks before aortic constriction.
Echocardiographic and morphometric analyses showed that Stim1 silencing by AAV9-mediated gene transfer protected rats from pressure overload-induced cardiac hypertrophy. Concordantly, cardiomyocyte size measured visually or by cellular capacitance was higher in CM isolated from pressure-overloaded hearts compared to sham, and Stim1 silencing resulted in significantly lower values.
Finally, nuclear translocation of NFATC3 was significantly reduced in AAV9shSTIM1 rat hearts.

Conclusion: STIM1 promotes cardiac hypertrophy by controlling a previously unrecognized sarcolemmal current. Taken together, our data demonstrate an important role for STIM1 in the progression of cardiac hypertrophy and suggest a possible role in cardiac disease.




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The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.