MicroRNA-1976 regulates degeneration of the sinoatrial node by targeting Cav1.2 and Cav1.3 ion channels

• Published in: Journal of molecular and cellular cardiology 2019-09, Vol.134, p.74-85
• Main Authors: Zhang, Jin, Wei, Feiyu, Ding, Liqun, Wang, Lilin, Zhang, Xi, Yu, Lin, Liu, Rui, Kuang, Xiaohui, Jiao, Baowei, Yang, Bin, Fan, Jie
• Format: Article
• Language: English
• Subjects: Ion channels; microRNA-1976; Sick sinus syndrome; Sinoatrial node aging
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2019.06.018

Sick sinus syndrome (SSS) is primarily a disease of the elderly, and age-dependent decrease in Cav1.2 and Cav1.3 Ca2+ channels within the sinus node has been shown to play an important role in sinoatrial node (SAN) degeneration; however, posttranscriptional mechanisms regulating decrease in Cav1.2 and Cav1.3 Ca2+ channels remain unclear. Some studies have reported that microRNAs (miRNAs) are involved in age-related cardiovascular diseases. Nevertheless, little is known about the roles of miRNAs in age-related SSS. This study investigated whether miR-1976 was involved in the regulation of SAN degeneration by targeting Cav1.2 and Cav1.3 Ca2+ channels. First, using microarray-based miRNA expression profiling and qRT-PCR, we confirmed that miR-1976 was upregulated in the plasma of patients with age-related SSS relative to healthy controls. By employing target gene prediction software, luciferase assay and western blotting, we further confirmed Cav1.2 and Cav1.3 as direct targets of miR-1976. Furthermore, miR-1976 levels in rabbit SAN tissues were negatively correlated with Cav1.2 and Cav1.3 expression and intrinsic heart rates but positively correlated with corrected sinus node recovery time (CSNRT). Additionally, miR-1976 transgenic mice displayed attenuated Cav1.2 and Cav1.3 protein expression, which led to sinus node dysfunction. These results suggest that miR-1976 plays an important role in the SAN aging process by targeting Cav1.2 and Cav1.3. Thus, miR-1976 could have great potential as a noninvasive diagnostic tool and therapeutic target for SSS. These findings may reveal important insights into the pathogenesis of SSS. •miR-1976 was upregulated in SSS patient plasma and animal SAN tissues and leading to SSS by targeting Cav1.2 and Cav1.3.•Cav1.2 and Cav1.3 are the direct targets of miR-1976 by employing target gene prediction software, lucifer's assay and western blotting.•The miR-1976 levels in rabbits SAN were correlated negatively with average heart rate and Cav1.2 and Cav1.3 expression, but correlated positively with corrected sinus node recovery time (CSNRT)•The miRNA-1976 transgenic mice remarkably attenuated Cav1.2,Cav1.3 protein expression and leaded to sinus node dysfunction.