Abstract 16719: STIM1 Inhibits GSK3-Beta to Maintain Cardiac Hypertrophy in a Murine Pressure Overload Induced Heart Failure Model
STromal Interaction Molecule 1 (STIM1) is the sensor of endoplasmic reticulum Ca2+ store in non-contractile cells. In cardiac myocytes (CM), we demonstrated that pressure-overload induced hypertrophy led to an increase in STIM1 expression and to the activation of STIM1-induced currents that promote CM hypertrophy.
Our objective was to further investigate the role of STIM1 in the transition to heart failure (HF). We performed Transverse Aortic Constriction surgery (TAC) on control and AAV9.shSTIM1 infected mice to induce cardiac hypertrophy and failure.
In a first approach, STIM1 was silenced before TAC. As compared to TAC-controls, TAC-shSTIM1-treated mice showed a complete prevention of the development of cardiac hypertrophy (IVSd, mm: 1.46±0.07 in control vs. 1.01±0.11 in shSTIM1 mice, p<0.001). This effect was however associated with a significant left ventricular (LV) contractile dysfunction and dilation.
In a second experiment, STIM1 silencing was performed after TAC at the time when mice had developed compensated hypertrophy. In the 5 weeks following AAV administration, AAV9.shSTIM1-treated mice were unable to maintain the established cardiac hypertrophy, which resulted in a rapid worsening in contractile dysfunction and the development of LV dilation (IVSd, mm: 1.45±0.23 vs. 1.04±0.14 and LVIDd, mm: 3.54±0.54 vs. 4.75±0.38 in control and shSTIM1 mice respectively; p<0.001).
Western blotting on total hearts and isolated CM from AAV9.shSTIM1-treated mice showed a profound reduction in AKT and GSK3β phosphorylation, thus suggesting GSK3β activation after STIM1 silencing. Concordantly, treatment with a GSK3β pharmacological inhibitor restored the ability of TAC-shSTIM1-treated mice to maintain cardiac hypertrophy and prevent the rapid transition to HF.
In a phospho-proteome profiling in HEK cells, we further observed that activation of STIM1-ORAI complex after thapsigargin-induced Ca2+ store depletion increased phosphorylation of AKT and GSK3β. Treatment of HEK cells with an ORAI inhibitor, blocking STIM1 dependent Ca2+ entry, led to decrease of phosphorylation of AKT and GSK3β.
These data support a model where activation of STIM1 promotes CM growth by repressing the anti-hypertrophic effects of GSK3β through regulation of AKT.
Author Disclosures: L.O. Bénard: None. D.S. Matasic: None. J. Oh: None. M. Nonnenmacher: None. E. Kohlbrenner: None. R.J. Hajjar: None. J. Hulot: None.
- © 2014 by American Heart Association, Inc.