Shelton Elaine L, Ector Gerren, Galindo Cristi L, Hooper Christopher W, Brown Naoko, Wilkerson Irene, Pfaltzgraff Elise R, Paria Bibhash C, Cotton Robert B, Stoller Jason Z, Reese Jeff
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee;
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
Physiol Genomics. 2014 Jul 1;46(13):457-66. doi: 10.1152/physiolgenomics.00171.2013. Epub 2014 May 1.
Failure of the ductus arteriosus (DA) to close at birth can lead to serious complications. Conversely, certain profound congenital cardiac malformations require the DA to be patent until corrective surgery can be performed. In each instance, clinicians have a very limited repertoire of therapeutic options at their disposal - indomethacin or ibuprofen to close a patent DA (PDA) and prostaglandin E1 to maintain patency of the DA. Neither treatment is specific to the DA and both may have deleterious off-target effects. Therefore, more therapeutic options specifically targeted to the DA should be considered. We hypothesized the DA possesses a unique genetic signature that would set it apart from other vessels. A microarray was used to compare the genetic profiles of the murine DA and ascending aorta (AO). Over 4,000 genes were differentially expressed between these vessels including a subset of ion channel-related genes. Specifically, the alpha and beta subunits of large-conductance calcium-activated potassium (BKCa) channels are enriched in the DA. Gain- and loss-of-function studies showed inhibition of BKCa channels caused the DA to constrict, while activation caused DA relaxation even in the presence of O2. This study identifies subsets of genes that are enriched in the DA that may be used to develop DA-specific drugs. Ion channels that regulate DA tone, including BKCa channels, are promising targets. Specifically, BKCa channel agonists like NS1619 maintain DA patency even in the presence of O2 and may be clinically useful.
出生时动脉导管（DA）未能闭合可导致严重并发症。相反，某些严重的先天性心脏畸形需要动脉导管保持开放直至能够进行矫正手术。在每种情况下，临床医生可选用的治疗方法都非常有限——用吲哚美辛或布洛芬来闭合开放的动脉导管（PDA），用前列腺素E1来维持动脉导管的通畅。这两种治疗方法都并非特异性针对动脉导管，而且都可能产生有害的脱靶效应。因此，应考虑更多专门针对动脉导管的治疗选择。我们推测动脉导管具有独特的基因特征，使其有别于其他血管。利用微阵列比较了小鼠动脉导管和升主动脉（AO）的基因图谱。这些血管之间有超过4000个基因差异表达，其中包括一部分与离子通道相关的基因。具体而言，大电导钙激活钾（BKCa）通道的α和β亚基在动脉导管中富集。功能获得和功能丧失研究表明，抑制BKCa通道会导致动脉导管收缩，而激活该通道即使在有氧的情况下也会使动脉导管舒张。本研究确定了在动脉导管中富集的基因子集，这些基因子集可用于开发针对动脉导管的药物。调节动脉导管张力的离子通道，包括BKCa通道，是很有前景的靶点。具体来说，像NS1619这样的BKCa通道激动剂即使在有氧的情况下也能维持动脉导管的通畅，可能具有临床应用价值。
