Troupes Constantine D, Wallner Markus, Borghetti Giulia, Zhang Chen, Mohsin Sadia, von Lewinski Dirk, Berretta Remus M, Kubo Hajime, Chen Xiongwen, Soboloff Jonathan, Houser Steven
From the Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (C.D.T., M.W., G.B., C.Z., S.M., R.M.B., H.K., X.C., S.H.); Department of Cardiology, Medical University of Graz, Austria (D.v.L.); and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University School of Medicine, Philadelphia, PA (J.S.).
Circ Res. 2017 Jul 7;121(2):125-136. doi: 10.1161/CIRCRESAHA.117.311094. Epub 2017 Jun 7.
Pathological increases in cardiac afterload result in myocyte hypertrophy with changes in myocyte electrical and mechanical phenotype. Remodeling of contractile and signaling Ca occurs in pathological hypertrophy and is central to myocyte remodeling. STIM1 (stromal interaction molecule 1) regulates Ca signaling in many cell types by sensing low endoplasmic reticular Ca levels and then coupling to plasma membrane Orai channels to induce a Ca influx pathway. Previous reports suggest that STIM1 may play a role in cardiac hypertrophy, but its role in electrical and mechanical phenotypic alterations is not well understood.
To define the contributions of STIM1-mediated Ca influx on electrical and mechanical properties of normal and diseased myocytes, and to determine whether Orai channels are obligatory partners for STIM1 in these processes using a clinically relevant large animal model of hypertrophy.
Cardiac hypertrophy was induced by slow progressive pressure overload in adult cats. Hypertrophied myocytes had increased STIM1 expression and activity, which correlated with altered Ca-handling and action potential (AP) prolongation. Exposure of hypertrophied myocytes to the Orai channel blocker BTP2 caused a reduction of AP duration and reduced diastolic Ca spark rate. BTP2 had no effect on normal myocytes. Forced expression of STIM1 in cultured adult feline ventricular myocytes increased diastolic spark rate and prolonged AP duration. STIM1 expression produced an increase in the amount of Ca stored within the sarcoplasmic reticulum and activated Ca/calmodulin-dependent protein kinase II. STIM1 expression also increased spark rates and induced spontaneous APs. STIM1 effects were eliminated by either BTP2 or by coexpression of a dominant negative Orai construct.
STIM1 can associate with Orai in cardiac myocytes to produce a Ca influx pathway that can prolong the AP duration and load the sarcoplasmic reticulum and likely contributes to the altered electromechanical properties of the hypertrophied heart.
心脏后负荷的病理性增加会导致心肌细胞肥大，并伴有心肌细胞电和机械表型的改变。收缩性和信号性钙的重塑发生在病理性肥大中，是心肌细胞重塑的核心。基质相互作用分子1（STIM1）通过感知内质网低钙水平，然后与质膜Orai通道偶联以诱导钙内流途径，从而调节多种细胞类型中的钙信号。先前的报道表明STIM1可能在心肌肥大中起作用，但其在电和机械表型改变中的作用尚不清楚。
使用临床相关的大型动物肥大模型，确定STIM1介导的钙内流对正常和患病心肌细胞电和机械特性的贡献，并确定Orai通道在这些过程中是否是STIM1的必需伴侣。
通过成年猫缓慢进行性压力超负荷诱导心脏肥大。肥大的心肌细胞中STIM1表达和活性增加，这与钙处理改变和动作电位（AP）延长相关。将肥大的心肌细胞暴露于Orai通道阻滞剂BTP2可导致AP持续时间缩短和舒张期钙火花率降低。BTP2对正常心肌细胞无影响。在培养的成年猫心室肌细胞中强制表达STIM1可增加舒张期火花率并延长AP持续时间。STIM1表达使肌浆网内储存的钙量增加，并激活钙/钙调蛋白依赖性蛋白激酶II。STIM1表达还增加了火花率并诱导自发AP。BTP2或显性负性Orai构建体的共表达消除了STIM1的作用。
STIM1可与心肌细胞中的Orai结合，产生一种可延长AP持续时间并使肌浆网负荷的钙内流途径，可能导致肥大心脏的机电特性改变。
