Bénard Ludovic, Oh Jae Gyun, Cacheux Marine, Lee Ahyoung, Nonnenmacher Mathieu, Matasic Daniel S, Kohlbrenner Erik, Kho Changwon, Pavoine Catherine, Hajjar Roger J, Hulot Jean-Sébastien
From Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.B., J.G.O., M.C., A.L., M.N., D.S.M., E.K., C.W.K., R.J.H., J.-S.H.); and Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Paris, France (C.P., J.-S.H.).
Circulation. 2016 Apr 12;133(15):1458-71; discussion 1471. doi: 10.1161/CIRCULATIONAHA.115.020678. Epub 2016 Mar 2.
Stromal interaction molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiomyocytes. 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.
To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiomyocytes by using in vivo gene delivery of specific short hairpin RNAs. In 3 different models, we found that Stim1 silencing prevents the development of pressure overload-induced hypertrophy but also reverses preestablished 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 antihypertrophic and proapoptotic GSK-3β molecule. Pharmacological inhibition of glycogen synthase kinase-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 Akt(S473), a hydrophobic motif of Akt that is directly phosphorylated by mTOR complex 2. We found that Stim1 silencing directly impaired mTOR complex 2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTOR complex 2.
These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiomyocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2, which further results in repression of GSK-3β activity.
基质相互作用分子1（STIM1）是一种动态钙信号转导分子，与心肌细胞肥大生长有关。STIM1被认为在肌膜水平上作为心脏肥大反应的启动因子，但支撑这种作用的信号通路尚未得到研究。
为了确定STIM1在心脏肥大及向心力衰竭转变过程中的机制作用，我们通过体内递送特定短发夹RNA来调控小鼠心肌细胞中STIM1的表达。在3种不同模型中，我们发现沉默Stim1可预防压力超负荷诱导的肥大发展，还能逆转已建立的心脏肥大。STIM1表达降低促进了向心力衰竭的快速转变。我们进一步表明，沉默Stim1导致抗肥大和促凋亡的GSK-3β分子活性增强。糖原合酶激酶-3的药理学抑制足以逆转沉默Stim1后观察到的心脏表型。在心室肌细胞水平，沉默或抑制Stim1消除了Akt（S473）磷酸化的能力，Akt的疏水基序由mTOR复合物2直接磷酸化。我们发现沉默Stim1直接损害了mTOR复合物2的激酶活性，这得到了STIM1与mTOR复合物2的特定组分Rictor之间直接相互作用的支持。
这些数据支持一种模型，即STIM1对于失活心脏肥大的关键负调节因子至关重要。在心肌细胞中，STIM1通过激活mTOR复合物2来调节Akt激酶活性，进而导致GSK-3β活性受到抑制。
