Abstract 313: STIM1 Silencing Reverses Pressure-overload Induced Cardiac Hypertrophy In Mice
STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways.
We demonstrated that STIM1 silencing prevented the development of left ventricular hypertrophy (LVH) in rats after abdominal aortic banding.
Our aim was to study the role of STIM1 during the transition from LVH to heart failure (HF). For experimental timeline, see figure.
Transverse Aortic Constriction (TAC) was performed in C57Bl/6 mice. In vivo gene silencing was performed using recombinant Associated AdenoVirus 9 (AAV9). Mice were injected with saline or with AAV9 expressing shRNA control or against STIM1 (shSTIM1) (dose: 1e+11 viral genome), which decreased STIM1 cardiac expression by 70% compared to control.
While cardiac parameters were similar between the TAC groups at weeks 3 and 6, shSTIM1 animals displayed a progressive and total reversion of LVH with LV walls thickness returning to values observed in sham mice at week 8. This reversion was associated with the development of significant LV dilation and severe contractile dysfunction, as assessed by echography. Hemodynamic analysis confirmed the altered contractile function and dilation of shSTIM1 animals. Immunohistochemistry showed a trend to more fibrosis. Despite hypertrophic stimuli, there was a significant reduction in cardiac myocytes cross-section area in shSTIM1-treated animals as compared to other TAC mice.
This study showed that STIM1 is essential to maintain compensatory LVH and that its silencing accelerates the transition to HF.
- © 2013 by American Heart Association, Inc.