【摘要】基质相互作用分子(stromal interaction molecule, STIM)1作为内质网内钙离子浓度的敏感感受器维持着细胞内的钙稳态，参与了多种心血管疾病的发生发展，对心血管疾病的预防有重大意义。
【关键词】基质相互作用分子1 SOCE Orai
目前，心血管疾病如高血压、冠心病等的发病率呈上升趋势，其具体发病机制尚不明确，参与其发生发展的病理生理基础仍不完全清楚。近年来，不少学者发现基质相互作用分子(stromal interaction molecule, STIM)1作为内质网内钙离子浓度的敏感感受器，当内质网内钙库消耗后, 通过与Orai偶联实现钙库操作性钙离子通道(store-operated calcium entry, SOCE)的功能开放,形成内向的Ca2+流以补充消耗的Ca2+。新近研究发现STIM1蛋白除了参与调节SOCE通路的开放与关闭, 也参与心血管疾病的发生发展。本文将就有关STIM1在心血管疾病中的研究进展作一综述。
一、STIM1和SOCE的分子调控
钙库操作性钙离子通道(store-operated calcium entry, SOCE)核心蛋白由位于内质网上的能感受Ca2+浓度变化的基质相互作用分子(stromal interaction molecule, STIM)和位于细胞膜上的Orai蛋白构成[1] ，当内质网内钙库中Ca2+消耗之后, STIM蛋白通过其特殊的结构能够感受内质网内钙库中Ca2+浓度的变化, 发生快速的转位和聚合化等激活反应, 与质膜上的Orai蛋白偶联, 实现SOCE通路的功能开放, 引起Ca2+内流。当钙库中Ca2+得到补充之后, STIM蛋白与Orai蛋白缓慢解离即失活, 通路关闭。
二、STIM1调控的SOCE在心脏中的生理作用
STIM1/SOCE通路除了参与心肌细胞肥大的发生发展过程及心肌细胞的收缩外，最近研究还发现，SOCE在心肌细胞的电稳定性的调解中起到重要的作用[[[] Wang P, Umeda PK, Sharifov OF, et al. Evidence that 2-aminoethoxy-diphenyl borate provokes fibrillation in perfused rat hearts via voltage-independent calcium channels. Eur J Pharmacol,2012, 681: 60 –67.]]。此外，Nguyen等[[[] Nguyen N, Biet M, Simard E, et al. STIM1 participates in the contractile rhythmicity of HL-1 cells by moderating T-type Ca2+ channel activity. Biochim Biophys Acta,2013,1833: 1294 –1303.]]表明，在HL1细胞中，STIM1表达的减少会影响细胞的收缩性，导致Ca2+失衡和心律失常的发生。Touchberry等[[[] Touchberry CD, Elmore CJ, Nguyen TM, et al. Store-operated calcium entry is present in HL-1 cardiomyocytes and contributes to resting calcium. Biochem Biophys Res Commun,2011,416:45–50.]]将HL1细胞的Orai1敲减后发现，STIM1/Orai1调控的SOCE在心肌细胞Ca2+平衡的维持中起到关键性的作用。以上试验说明STIM1调控的SOCE在心脏中有着重要的生理作用，而其在心肌细胞中的具体作用机制尚有待进步试验的探讨。
三、STIM1与血管增殖性疾病
血管增殖性疾病中最主要的是经皮冠状动脉介入治疗和支架植入术后造成的血管内皮损伤而诱导的血管再狭窄。再狭窄的主要原因是术后新生内膜肥厚所致，而新生内膜大部分是因平滑肌细胞增殖迁移引起。在血管内皮损伤后，平滑肌细胞暴露于生长因子并开始增殖和向受损处迁移，形成新生内膜，从而导致术后再狭窄。通过大鼠颈动脉球囊损伤模型发现[[[] W.Zhang, K.E.Halligan,X.Zhang, et al. Orai1-Mediated ICRAC Is Essential for Neointima Formation After Vascular Injury. Circ Res, 2011,109(5), 534-42.]]，STIM1可以诱导血管平滑肌细胞（VSMC)增殖，而用RNA干扰抑制STIM1基因表达可以阻止新生内膜肥厚。在人类肺动脉平滑肌中，血小板源性生长因子PDGF可通过上调STIM1和Orai1导致SOCE明显增加[[[] A.Ogawa, A.L.Firth, K.A.Smith, et al. PDGF enhances store-operated Ca2+ entry by upregulating STIM1/Orai1 via activation of Akt/mTOR in human pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol,2012, 302(2), C405-11.]]。因此推测，STIM1参与了支架植入术后血管再狭窄的发生发展过程，有望成为防治术后血管再狭窄的新靶标。
四、STIM1与心脏肥大
Luo等[[[] Luo X, Hojayev B, Jiang N, et al. STIM1-dependent store-operated Ca2+ entry is required for pathological cardiac hypertrophy. J Mol Cell Cardiol,2012, 52: 136 –147.]]研究发现在成人心脏中STIM1水平是低的，但是在经主动脉收缩而诱导心脏肥大后，STIM1表达量明显升高而且伴随着显著增强的SOCE电流。在心肌细胞中转染了已被活化的STIM1后，足以导致细胞肥大和蛋白质的合成，同时加用生理激动剂苯肾上腺素（PE）刺激，这种效应会进一步增强。此外，Hulot等[[[] Hulot JS, Fauconnier J, Ramanujam D, et al. Critical role for stromal interaction molecule 1 in cardiac hypertrophy. Circulation, 2011, 124: 796 –805.]]报道，不仅是在体外，在体内成年鼠心脏中，STIM1也参与了心肌细胞肥大的发生发展，然而沉默的STIM1基因可以使心脏免遭因压力负荷过重所致的肥大的发生。所有的这些研究都强烈的支持了STIM1，尤其是STIM1调控的SOCE在心肌肥大中发挥着关键性作用。
五、STIM1与缺血/再灌注损伤
钙超载在急性心肌缺血/再灌注损伤中起重要的作用。Valverde等[[[] Valverde CA, Kornyeyev D, Ferreiro M, et al. Transient Ca2+ depletion of the sarcoplasmic reticulum at the onset of reperfusion. Cardiovasc Res,2010,85: 671–680.]]对离体心脏进行缺血/再灌注试验，发现内质网钙库的Ca2+水平明显减少，而这也正是活化STIM1导致SOCE通路开放的关键步骤。将SOCE的药物抑制剂Gd3+和2-氨基乙氧基本硼酸(2-APB)应用于受到缺血/再灌注损伤的心脏微血管内皮细胞，可以遏制钙超载的发生，这更进一步说明了SOCE通路在缺血/再灌注损伤所致的钙超载中的作用。
缺血/再灌注损伤的后果之一是增加室性心律失常的发生率；初步研究表明[[[] Wen H, Zhao Zhenghang, Fefelova Nadezhda, et al. Arrhythmogenic effect of store-operated calcium entry in mouse ventricular myocytes (Abstract). Circulation,2011,124: A15884.]]，成年鼠的心肌细胞在缺血的环境下，自发性Ca2+释放会增加，这一现象可以被Gd3+（一种SOCE抑制剂）所阻断，说明自发性Ca2+的释放和从而所致的心律失常这一过程，至少有一部分被SOCE调解。与先前的研究一致，STIM1/Orai1调控的SOCE的增加会促发房性和室性心律失常[2]。所以，许多试验都证实了STIM1调控的SOCE通路在缺血/再灌注损伤中扮演着重要的角色，希望有更多的学者能够进步了解STIM1与缺血/再灌注损伤的关系，从而增加再灌注治疗的成功率。
六、STIM1与心肌细胞的新陈代谢
早在1995年，Marchase[[[] Rivera AA, White CR, Guest LL, et al. Hyperglycemia alters cytoplasmic Ca2+ responses to capacitative Ca2+ influxin rat aortic smooth muscle cells. Am J Physiol Cell Physiol,1995,269:C1482–C1488.]]等报道，平滑肌细胞膜的SOCE可以被高血糖抑制，在接下来的试验中，他们发现上诉现象也发生于巨噬细胞和心肌细胞。近年来研究发现[[[] Jardin I, Lopez JJ, Zbidi H, et al.Attenuated store-operated divalent cation entry and association between STIM1, Orai1, hTRPC1 and hTRPC6 in platelets from type 2 diabetic patients. Blood Cells Mol Dis,2011,46: 252–260.]]，2型糖尿病病人的血小板膜上的SOCE是减少的。
期刊文章分类查询,尽在期刊图书馆此外，Marsh等[[[] Marsh SA, Dell'Italia LJ, Chatham JC. Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice. Amino Acids, 2011,40: 819 –828.]]报道了在心肌细胞中，依赖SOCE的致肥大信号在患有糖尿病的小鼠体中是减弱的。Estrada等[[[] Estrada IA, Donthamsetty R, Debski P, et al. STIM1 restores coronary endothelial function in type 1 diabetic mice. Circ Res,2012,111: 1166 –1175.]]试验证明，与正常组相比，糖尿病组小鼠的内皮细胞的STIM1蛋白水平明显降低。他们还发现，当正常动物体内的细胞处于高糖环境中时，STIM1水平将发生于糖尿病组相似的变化。
除了在细胞供能中起主要作用外，线粒体也通过调解活性氧和细胞质内Ca2+水平来维持细胞内稳态。Henke等[[[] Henke N, Albrecht P, Pfeiffer A, et al. Stromal interaction molecule 1 (STIM1) is involved in the regulation of mitochondrial shape and bioenergetics and plays a role in oxidative stress. J Biol Chem,2012,287: 42042–42052.]]发现，敲减STIM1和Orai1会增加细胞对氧化应激的敏感性。此外，他们发现在STIM1缺如的细胞中，线粒体的结构遭到破坏。实验说明了STIM1参与线粒体平衡和氧化应激的调节。
STIM1作为内质网内钙离子浓度的敏感感受器维持着细胞内的钙稳态，除了参与以上心血管疾病的发生发展外，尚有研究表明STIM1与高血压的血管舒缩功能障碍[[[] Giachini FR，Chiao CW，Carneiro FS，et al. Increased activation of stromal interaction molecule-1 /Orai-1 in aorta from hypertensive rats: a novel insight into vascular dysfunction［J］.Hypertension，2009，53( 2) : 409-416．]]、血小板的活化和血栓形成[[[] Ambily A, Kaiser WJ, Pierro C, et al. The role of plasma membrane STIM1 and Ca(2+)entry in platelet aggregation.STIM1 binds to novel proteins in human platelets. Cell Signal,2014,26(3):502-11.]]、内皮祖细胞的增殖和分化[[[] Sanchez-Hernandez Y，Laforenza U，Bonetti E，et al．Store-operated Ca2+ entry is expressed in human endothelial progenitor cells［J］.Stem Cells Dev，2010，19( 12) :1967-1981．]]等密切相关。随着人们对STIM1在心血管疾病中的作用及其作用机制的深入研究，其必将成为心血管疾病的一个重要的治疗靶点。
【参考文献】
[1] Várnai P, Hunyady L, Balla T. STIM and Orai: the long-awaited constituents of store-operated calcium entry. Trends Pharmac Sci,2009, 30(3): 118-28.
[2] Wang P, Umeda PK, Sharifov OF, et al. Evidence that 2-aminoethoxy-diphenyl borate provokes fibrillation in perfused rat hearts via voltage-independent calcium channels. Eur J Pharmacol,2012, 681: 60 –67.
[3] Nguyen N, Biet M, Simard E, et al. STIM1 participates in the contractile rhythmicity of HL-1 cells by moderating T-type Ca2+ channel activity. Biochim Biophys Acta,2013,1833: 1294 –1303.
[4] Touchberry CD, Elmore CJ, Nguyen TM, et al. Store-operated calcium entry is present in HL-1 cardiomyocytes and contributes to resting calcium. Biochem Biophys Res Commun,2011,416:45–50.
[5] W.Zhang, K.E.Halligan,X.Zhang, et al. Orai1-Mediated ICRAC Is Essential for Neointima Formation After Vascular Injury. Circ Res, 2011,109(5), 534-42.
[6] A.Ogawa, A.L.Firth, K.A.Smith, et al. PDGF enhances store-operated Ca2+ entry by upregulating STIM1/Orai1 via activation of Akt/mTOR in human pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol,2012, 302(2), C405-11.
[7] Luo X, Hojayev B, Jiang N, et al. STIM1-dependent store-operated Ca2+ entry is required for pathological cardiac hypertrophy. J Mol Cell Cardiol,2012, 52: 136 –147.
[8] Hulot JS, Fauconnier J, Ramanujam D, et al. Critical role for stromal interaction molecule 1 in cardiac hypertrophy. Circulation, 2011, 124: 796 –805.
[] Valverde CA, Kornyeyev D, Ferreiro M, et al. Transient Ca2+ depletion of the sarcoplasmic reticulum at the onset of reperfusion. Cardiovasc Res,2010,85: 671–680.
[9] Wen H, Zhao Zhenghang, Fefelova Nadezhda, et al. Arrhythmogenic effect of store-operated calcium entry in mouse ventricular myocytes (Abstract). Circulation,2011,124: A15884.
[10] Rivera AA, White CR, Guest LL, et al. Hyperglycemia alters cytoplasmic Ca2+ responses to capacitative Ca2+ influxin rat aortic smooth muscle cells. Am J Physiol Cell Physiol,1995,269:C1482–C1488.
[11] Jardin I, Lopez JJ, Zbidi H, et al.Attenuated store-operated divalent cation entry and association between STIM1, Orai1, hTRPC1 and hTRPC6 in platelets from type 2 diabetic patients. Blood Cells Mol Dis,2011,46: 252–260.
[12] Marsh SA, Dell'Italia LJ, Chatham JC. Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice. Amino Acids, 2011,40: 819 –828.
[13] Estrada IA, Donthamsetty R, Debski P, et al. STIM1 restores coronary endothelial function in type 1 diabetic mice. Circ Res,2012,111: 1166 –1175.
[14] Henke N, Albrecht P, Pfeiffer A, et al. Stromal interaction molecule 1 (STIM1) is involved in the regulation of mitochondrial shape and bioenergetics and plays a role in oxidative stress. J Biol Chem,2012,287: 42042–42052.
[15] Giachini FR，Chiao CW，Carneiro FS，et al. Increased activation of stromal interaction molecule-1 /Orai-1 in aorta from hypertensive rats: a novel insight into vascular dysfunction［J］.Hypertension，2009，53( 2) : 409-416．
[16] Ambily A, Kaiser WJ, Pierro C, et al. The role of plasma membrane STIM1 and Ca(2+)entry in platelet aggregation.STIM1 binds to novel proteins in human platelets. Cell Signal,2014,26(3):502-11.
[17] Sanchez-Hernandez Y，Laforenza U，Bonetti E，et al．Store-operated Ca2+ entry is expressed in human endothelial progenitor cells［J］.Stem Cells Dev，2010，19( 12) :1967-1981．
论文作者:郏红静 过高峰
论文发表刊物:《临床医学教育》2017年6月
论文发表时间:2017/6/26
标签：细胞论文; 心肌论文; 内质网论文; 损伤论文; 作用论文; 发生论文; 血管论文; 《临床医学教育》2017年6月论文;