SCN5A: the greatest HITS collection

Abstract

Heart failure (HF) has been referred to as the cardiovascular epidemic of our time. Understanding the molecular determinants of HF disease progression and mortality risk is of utmost importance. In this issue of the JCI, Zhang et al. uncover an important link between clinical HF mortality risk and a common variant that regulates SCN5A expression through microRNA-dependent (miR-dependent)mechanisms. They also demonstrate that haploinsufficiency of SCN5A is associated with increased accumulation of reactive oxygen species (ROS) in a genetically engineered murine model. Their data suggest that even modest depression of SCN5A expression may promote pathologic cardiac remodeling and progression of HF.

Figure 1. Proposed link between microRNA-dependent regulation of SCN5A and disease progression.

Genome-wide association studies (GWAS) have linked a synonymous SNP (rs1805126) in the SCN5A gene with electrocardiographic measures. (A) Ago2 HITS-CLIP data identify a microRNA-24 (miR-24) binding site immediately adjacent to this SNP. (B) Probability of Interaction by Target Accessibility (PITA) analysis indicates that the rs1805126 minor allele (C) is a thermodynamically more favorable miR-24 target compared to the major allele (T), resulting in greater SCN5A degradation and diminished Na_V1.5 expression. While conduction slowing is a predictable consequence of diminished sodium channel expression, Zhang and colleagues (22) show, surprisingly, that reduced SCN5A expression is also associated with increased myocardial reactive oxygen species (ROS), and suggest that ROS accumulation promotes heart failure progression and increased nonarrhythmic mortality.