Sano Tomoya, Yasuno Hironobu, Watanabe Takeshi
Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
J Toxicol Pathol. 2021 Jul;34(3):223-230. doi: 10.1293/tox.2020-0089. Epub 2021 Apr 18.
There are limited data on the gene expression profiles of ion channels in the sinoatrial node (SAN) of dogs and monkeys. In this study, the messenger RNA (mRNA) expression profiles of various ion channels in the SAN of naïve dogs and monkeys were examined using RNAscope hybridization and compared with those in the surrounding right atrium (RA) of each species. Regional-specific Cav1.3 and HCN4 expression was observed in the SAN of dogs and monkeys. Additionally, HCN1 in dogs was only expressed in the SAN. The expression profiles of Cav3.1 and Cav3.2 in the SAN and RA were completely different between dogs and monkeys. Dog hearts only expressed Cav3.2; however, Cav3.1 was detected only in monkeys, and the expression score in the SAN was slightly higher than that in the RA. Although Kir3.1 and NCX1 in dogs were equally expressed in both the SAN and RA, the expression scores of these genes in the SAN of monkeys were slightly higher than those in the RA. The Kir3.4 expression score in the SAN of dogs and monkeys was also slightly higher than that in the RA. The mRNA expression scores of Kv11.1/ERG and KvLQT1 were equally observed in both the SAN and RA of dogs and monkeys. HCN2 was not detected in dogs and monkeys. In summary, we used RNAscope to demonstrate the SAN-specific gene expression patterns of ion channels, which may be useful in explaining the effect of pacemaking and/or hemodynamic effects in nonclinical studies.
关于犬和猴窦房结（SAN）中离子通道基因表达谱的数据有限。在本研究中，使用RNAscope杂交技术检测了未处理的犬和猴窦房结中各种离子通道的信使核糖核酸（mRNA）表达谱，并与每个物种周围右心房（RA）中的表达谱进行了比较。在犬和猴的窦房结中观察到区域特异性的Cav1.3和HCN4表达。此外，犬的HCN1仅在窦房结中表达。犬和猴的窦房结和右心房中Cav3.1和Cav3.2的表达谱完全不同。犬心脏仅表达Cav3.2；然而，Cav3.1仅在猴中检测到，且在窦房结中的表达评分略高于右心房。虽然犬的Kir3.1和NCX1在窦房结和右心房中表达水平相同，但这些基因在猴窦房结中的表达评分略高于右心房。犬和猴窦房结中Kir3.4的表达评分也略高于右心房。犬和猴的窦房结和右心房中均观察到Kv11.1/ERG和KvLQT1的mRNA表达评分相同。在犬和猴中未检测到HCN2。总之，我们使用RNAscope证明了离子通道的窦房结特异性基因表达模式，这可能有助于解释非临床研究中的起搏作用和/或血流动力学效应。
