Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter
Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter
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DOI：
10.1152/ajpheart.00170.2010
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发表时间：
2010-09-01
影响因子：
4.8
通讯作者：
Blakely, Randy D.
中科院分区：
文献类型：
--
作者：
English, Brett A.;Appalsamy, Martin;Blakely, Randy D.
英语BA，Appalsamy M，Diedrich A，Ruggiero AM，Lund D，Wright J，Keller NR，Louderback Km，Robertson D，Blakely RD.由于突触前胆碱转运体表达减少而引起的心动过速、迷走神经容量减少和年龄相关性心功能障碍。Am J Physiol心脏圈Physiol 299：H799-H810,2010。2010年7月2日首次出版；doi：10.1152/ajpheart.00170.2010。-健康的心血管功能依赖于心脏去甲肾上腺素能和胆碱能神经的平衡和反应整合。胆碱能终末的高亲和力胆碱摄取对ACh的高效产生和释放起着关键作用。到目前为止，胆碱转运蛋白(CHT)表达减少对心血管的影响还没有被直接研究，这主要是由于该转运蛋白在体内无法获得。在这里，我们描述了使用携带CHT基因缺陷的转基因小鼠进行的心血管实验的结果。CHT基因敲除(CHT-/-)小鼠表现出出生后早期死亡，而CHT杂合子(CHT+/-)小鼠存活、生长和繁殖正常，并表现出正常的自发行为。然而，CHT+/-小鼠心脏高亲和力胆碱摄取水平显著降低，同时ACh水平显著降低。这些小鼠的心血管功能的远程记录显示休息时有心动过速和高血压。在跑步机运动后，CHT+/-小鼠表现出较慢的心率恢复，与胆碱能储备减少一致，这一论点通过直接迷走神经刺激得到证实。超声心动图和组织学实验显示，随着年龄的增长，左室短轴缩短率降低，左心室内径增大，左室纤维化增加，与心功能不全相一致。CHT+/-小鼠的这些心血管表型鼓励对CHT表达降低的人类进行评估，以了解他们在维持正常心脏功能方面的弹性以及心血管疾病的风险。
English BA, Appalsamy M, Diedrich A, Ruggiero AM, Lund D, Wright J, Keller NR, Louderback KM, Robertson D, Blakely RD. Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter. Am J Physiol Heart Circ Physiol 299: H799-H810, 2010. First published July 2, 2010; doi:10.1152/ajpheart.00170.2010.-Healthy cardiovascular function relies on a balanced and responsive integration of noradrenergic and cholinergic innervation of the heart. High-affinity choline uptake by cholinergic terminals is pivotal for efficient ACh production and release. To date, the cardiovascular impact of diminished choline transporter (CHT) expression has not been directly examined, largely due to the transporter's inaccessibility in vivo. Here, we describe findings from cardiovascular experiments using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (CHT-/-) mice exhibit early postnatal lethality, CHT heterozygous (CHT+/-) mice survive, grow, and reproduce normally and exhibit normal spontaneous behaviors. However, the CHT+/- mouse heart displays significantly reduced levels of high-affinity choline uptake accompanied by significantly reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice revealed tachycardia and hypertension at rest. After treadmill exercise, CHT+/- mice exhibited slower heart rate recovery, consistent with a diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Echocardiographic and histological experiments revealed an age-dependent decrease in fractional shortening, increased left ventricular dimensions, and increased ventricular fibrosis, consistent with ventricular dysfunction. These cardiovascular phenotypes of CHT+/- mice encourage an evaluation of humans bearing reduced CHT expression for their resiliency in maintaining proper heart function as well as risk for cardiovascular disease.