MicroRNA-1976 regulates degeneration of the sinoatrial node by targeting Ca v 1.2 and Ca v 1.3 ion channels

• Published in: Journal of molecular and cellular cardiology 2019-09, Vol.134, p.74
• 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: Aged; Aged, 80 and over; Animals; Calcium Channels, L-Type - metabolism; Case-Control Studies; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs - metabolism; Middle Aged; Rabbits; Sick Sinus Syndrome - metabolism; Sinoatrial Node - metabolism
• ISSN: 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 Ca 1.2 and Ca 1.3 Ca channels within the sinus node has been shown to play an important role in sinoatrial node (SAN) degeneration; however, posttranscriptional mechanisms regulating decrease in Ca 1.2 and Ca 1.3 Ca 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 Ca 1.2 and Ca 1.3 Ca 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 Ca 1.2 and Ca 1.3 as direct targets of miR-1976. Furthermore, miR-1976 levels in rabbit SAN tissues were negatively correlated with Ca 1.2 and Ca 1.3 expression and intrinsic heart rates but positively correlated with corrected sinus node recovery time (CSNRT). Additionally, miR-1976 transgenic mice displayed attenuated Ca 1.2 and Ca 1.3 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 Ca 1.2 and Ca 1.3. 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.