Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function

Am J Physiol Heart Circ Physiol. 2014 Apr 15;306(8):H1231-9. doi: 10.1152/ajpheart.00075.2014. Epub 2014 Feb 28.


The endoplasmic reticulum (ER) Ca(2+) sensor stromal interaction molecule 1 (STIM1) has been implicated as a key mediator of store-dependent and store-independent Ca(2+) entry pathways and maintenance of ER structure. STIM1 is present in embryonic, neonatal, and adult cardiomyocytes and has been strongly implicated in hypertrophic signaling; however, the physiological role of STIM1 in the adult heart remains unknown. We, therefore, developed a novel cardiomyocyte-restricted STIM1 knockout ((cr)STIM1-KO) mouse. In cardiomyocytes isolated from (cr)STIM1-KO mice, STIM1 expression was reduced by ∼92% with no change in the expression of related store-operated Ca(2+) entry proteins, STIM2, and Orai1. Immunoblot analyses revealed that (cr)STIM1-KO hearts exhibited increased ER stress from 12 wk, as indicated by increased levels of the transcription factor C/EBP homologous protein (CHOP), one of the terminal markers of ER stress. Transmission electron microscopy revealed ER dilatation, mitochondrial disorganization, and increased numbers of smaller mitochondria in (cr)STIM1-KO hearts, which was associated with increased mitochondrial fission. Using serial echocardiography and histological analyses, we observed a progressive decline in cardiac function in (cr)STIM1-KO mice, starting at 20 wk of age, which was associated with marked left ventricular dilatation by 36 wk. In addition, we observed the presence of an inflammatory infiltrate and evidence of cardiac fibrosis from 20 wk in (cr)STIM1-KO mice, which progressively worsened by 36 wk. These data demonstrate for the first time that STIM1 plays an essential role in normal cardiac function in the adult heart, which may be important for the regulation of ER and mitochondrial function.

Keywords: ER stress; STIM1; cardiomyocytes; mitochondria; store-operated Ca2+ entry.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium Channels
  • Cardiomyopathy, Dilated / etiology
  • Endoplasmic Reticulum / physiology*
  • Endoplasmic Reticulum Stress
  • Heart / physiology*
  • Homeostasis
  • Male
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria, Heart / physiology*
  • Mitochondria, Heart / ultrastructure
  • Myocytes, Cardiac / chemistry
  • Stromal Interaction Molecule 1
  • Ventricular Function, Left


  • Calcium Channels
  • Membrane Glycoproteins
  • Stim1 protein, mouse
  • Stromal Interaction Molecule 1