Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, China; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, China; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China; National key laboratory of frigid cardiovascular disease, Harbin, China.
Biomed Pharmacother. 2023 Sep;165:115267. doi: 10.1016/j.biopha.2023.115267. Epub 2023 Aug 4.
Cardiac ventricular arrhythmia triggered by acute myocardial infarction (AMI) is a major cause of sudden cardiac death. We have reported previously that an increased serum level of circular RNA CDR1as is a potential biomarker of AMI. However, the possible role of CDR1as in post-infarct arrhythmia remains unclear. This study in MI mice investigated the effects and underlying mechanism of CDR1as in ventricular arrhythmias associated with MI. We showed that knockdown of CDR1as abbreviated the duration of the abnormally prolonged QRS complex and QTc intervals and decreased susceptibility to ventricular arrhythmias. Optical mapping demonstrated knockdown of CDR1as also reduced post-infarct arrhythmia by increasing the conduction velocity and decreasing dispersion of repolarization. Mechanistically, CDR1as led to the depletion of NAD and caused mitochondrial dysfunction by directly targeting the NAMPT protein and repressing its expression. Moreover, CDR1as aggravated dysregulation of the Na1.5 and Kir6.2 channels in cardiomyocytes, a change which was alleviated by the replenishment of NAD. These findings suggest that anti-CDR1as is a potential therapeutic approach for ischemic arrhythmias.
急性心肌梗死（AMI）引起的心室性心律失常是心源性猝死的主要原因。我们之前曾报道过，循环 RNA CDR1as 血清水平升高是 AMI 的潜在生物标志物。然而，CDR1as 在梗死后心律失常中的可能作用尚不清楚。本研究在 MI 小鼠中探讨了 CDR1as 在与 MI 相关的室性心律失常中的作用及其潜在机制。我们发现，CDR1as 的敲低缩短了异常延长的 QRS 复合物和 QTc 间隔的持续时间，并降低了对室性心律失常的易感性。光学映射表明，CDR1as 的敲低还通过增加传导速度和降低复极离散度来减少梗死后心律失常。机制上，CDR1as 通过直接靶向 NAMPT 蛋白并抑制其表达导致 NAD 的耗竭和线粒体功能障碍。此外，CDR1as 加重了心肌细胞中 Na1.5 和 Kir6.2 通道的失调，而 NAD 的补充缓解了这种失调。这些发现表明，抗 CDR1as 是一种潜在的治疗缺血性心律失常的方法。
