MicroRNA-1976 regulates degeneration of the sinoatrial node by targeting Ca_v1.2 and Ca_v1.3 ion channels

Sick sinus syndrome (SSS) is primarily a disease of the elderly, and age-dependent decrease in Ca_v1.2 and Ca_v1.3 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 Ca_v1.2 and Ca_v1.3 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 Ca_v1.2 and Ca_v1.3 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 Ca_v1.2 and Ca_v1.3 as direct targets of miR-1976. Furthermore, miR-1976 levels in rabbit SAN tissues were negatively correlated with Ca_v1.2 and Ca_v1.3 expression and intrinsic heart rates but positively correlated with corrected sinus node recovery time (CSNRT). Additionally, miR-1976 transgenic mice displayed attenuated Ca_v1.2 and Ca_v1.3 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_v1.2 and Ca_v1.3. 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.