钙通过反向模式钠钙交换器进入有助于动脉损伤后储存操纵通道介导的新生内膜形成。
Ca Entry Through Reverse Mode Na/Ca Exchanger Contributes to Store Operated Channel-Mediated Neointima Formation After Arterial Injury.
机构信息
Department of Obstetrics and Gynecology, Kunming General Hospital, Kunming, Yunnan, China.
Division of Cardiovascular Surgery, and Department of Physiology, Mayo Clinic, Rochester, Minnesota, USA.
出版信息
Can J Cardiol. 2018 Jun;34(6):791-799. doi: 10.1016/j.cjca.2018.01.012. Epub 2018 Jan 31.
BACKGROUND
Na/Ca exchange (NCX) reversal-mediated Ca entry is a critical pathway for stimulating proliferation in many cell lines. However, the role of reverse-mode NCX1 in neointima formation and atherosclerosis remains unclear. The aims of the present study were to investigate the functional role of NCX1 in the pathogenesis of atherosclerosis and vascular smooth muscle cell (VSMC) proliferation, and to determine the interaction between NCX1 and store depletion in VSMCs.
METHODS
A rat balloon injury model was established to examine the effect of the knockdown of NCX1 on neointima formation after injury. VSMCs were cultured to verify that NCX1 knockdown suppressed serum-induced VSMC proliferation.
RESULTS
The results showed that balloon injury induced neointima formation and upregulated NCX1 expression at 7 and 14 days after injury in rat carotid arteries (1.18- and 1.45-fold, respectively). A lentivirus vector expressing short hairpin (sh)RNA against rat NCX1 dramatically downregulated NCX1, proliferating cell nuclear antigen (PCNA) and Ki-67 expression, and suppressed neointima formation in vivo (62% at 7 days and 70% at 14 days). KB-R7943 (an inhibitor of reverse-mode NCX1) and NCX1 knockdown significantly inhibited serum-induced VSMC proliferation (65% at 72 hours and 41% at 72 hours, respectively), determined according to PCNA and Ki-67 expression and cell counting in vitro, and markedly suppressed store depletion-mediated Ca entry and peripheral cytosolic Na transients in VSMCs.
CONCLUSIONS
Reverse-mode NCX1 is activated by store depletion and is required for proliferative VSMC proliferation and neointima formation after arterial injury.
背景
钠/钙交换（NCX）反向介导的钙内流是许多细胞系增殖的关键途径。然而，反向模式 NCX1 在新生内膜形成和动脉粥样硬化中的作用尚不清楚。本研究旨在探讨 NCX1 在动脉粥样硬化发病机制和血管平滑肌细胞（VSMC）增殖中的功能作用，并确定 NCX1 与 VSMCs 中储存耗竭之间的相互作用。
方法
建立大鼠球囊损伤模型，以研究 NCX1 敲低对损伤后新生内膜形成的影响。培养 VSMCs 以验证 NCX1 敲低抑制血清诱导的 VSMC 增殖。
结果
结果表明，球囊损伤诱导新生内膜形成，并在大鼠颈总动脉损伤后 7 天和 14 天分别上调 NCX1 表达（分别为 1.18 倍和 1.45 倍）。表达短发夹（sh）RNA 针对大鼠 NCX1 的慢病毒载体可显著下调 NCX1、增殖细胞核抗原（PCNA）和 Ki-67 的表达，并抑制体内新生内膜形成（7 天 62%，14 天 70%）。KB-R7943（反向模式 NCX1 的抑制剂）和 NCX1 敲低明显抑制血清诱导的 VSMC 增殖（72 小时时分别为 65%和 41%），根据体外 PCNA 和 Ki-67 表达和细胞计数确定，并显著抑制 VSMCs 中储存耗竭介导的 Ca 内流和外周胞质 Na 瞬变。
结论
反向模式 NCX1 被储存耗竭激活，是动脉损伤后增殖性 VSMC 增殖和新生内膜形成所必需的。
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