Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Abstract

Background STromal Interaction Molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiac myocytes. STIM1 is thought to act as an initiator of cardiac hypertrophic response at the level of the sarcolemma but the pathways underpinning this effect have not been examined. Methods and Results To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiac myocytes using in vivo gene delivery of specific short hairpin RNAs. In three different models, we found that Stim1 silencing prevents the development of pressure-overload induced hypertrophy but also reverses pre-established cardiac hypertrophy. Reduction in STIM1 expression promoted a rapid transition to heart failure. We further showed that Stim1 silencing resulted in enhanced activity of the anti-hypertrophic and pro-apoptotic GSK-3β molecule. Pharmacological inhibition of GSK-3 was sufficient to reverse the cardiac phenotype observed after Stim1 silencing. At the level of ventricular myocytes, Stim1 silencing or inhibition abrogated the capacity for phosphorylation of AktS473, a hydrophic motif of Akt that is directly phosphorylated by mTORC2. We found that Stim1 silencing directly impaired mTORC2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTORC2 complex. Conclusions These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiac myocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2 (mTORC2), which further results in repression of GSK-3β activity.

Salvianolic Acid B Alleviates Heart Failure by Inactivating ERK1/2/GATA4 Signaling Pathway after Pressure Overload in Mice

“…To investigate potential mechanisms of SalB's protection against the pressure-overload-induced HF, we focused on ERK1/2 and AKT, which are two major signaling pathways involved in HF [13]. Using Western blot analysis, we found that the ERK1/2 phophsrylations of threonines at 202 th and tyrosine at 204 th sites were enhanced after TAC surgery, compared with control(Fig 4A and 4C, P< 0.001).…”

Overexpression of SARAF Ameliorates Pressure Overload–Induced Cardiac Hypertrophy Through Suppressing STIM1-Orai1 in Mice

“…Although excessive activation of STIM1 and Orai1 is involved in the development of cardiac hypertrophy, basal activity of these two proteins are essential for responding to physiological stimuli and maintaining homeostasis of the myocardium. Gene silencing study demonstrated that basal level of STIM1 is critical for cardiac adaptive hypertrophy under physiological conditions and knocking down STIM1 led to progressive cardiac dilation and dysfunction [12]. Knockout of Orai1 induced dilated cardiomyopathy in pressure overloaded mice [13], suggesting Orai1 is also essential for cardiac hypertrophy to counteract pressure overload.…”

“…These findings suggest that suppressing STIM1/Orai1 could be a therapeutic strategy for preventing cardiac hypertrophy. Basal levels of STIM1/Orai1 may be essential for adaptive cardiac hypertrophy and maintain normal heart function, as loss of STIM1 or Orai1 promoted the development of dilated cardiomyopathy and heart failure [12][13][14]. It is difficult to find a balance between the anti-hypertrophic and the detrimental effects of STIM1/Orai1 knockdown.…”

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

“…SOCE has also emerged as a potential mechanism to alter Ca 2ϩ in the cardiomyocyte. It is greatly recognized that Ca 2ϩ entry through TRPC1, -C3, -C4, and -C6 channels and STIM1, by changing the fetal gene program governed by calcineurin/NFAT signaling, which is a characteristic of stressed cardiomyocytes, contributes to the pathogenesis of hypertrophy and HF (11,14,15,(21)(22)(23)(24)(25)(26). Additionally, many studies speculate the potential deleterious effect of SOCs in atrial and ventricular arrhythmias (27, 29, 31, 32).…”