Age-associated Alterations In Sialylation Affect Nav1.5 Channel Function And Contribute To Cardiac Dysfunction

Voltage-gated sodium channel Nav1.5 plays a pivotal role in the proper functioning of cardiac muscle cells by mediating their depolarization. Sialylation, a post-translational modification involving the addition of negatively charged sialic acid moieties, is essential for Nav1.5 functionality. Altered sialylation has been observed in various cardiovascular diseases, including Chagas disease, and congenital disorders of glycosylation affecting the heart. Furthermore, sialylation status has been shown to change during human adult life, impacting brain and muscle structural properties. Cardiac arrhythmias increase in prevalence with age, contributing to higher morbidity and mortality in the elderly. We aimed to investigate the impact of age-related changes in sialylation on Nav1.5 channels in cardiac cells. The Nav1.5 protein and sialic acid (α-2,3 and α-2,6) levels were quantified using SNA and MAA lectins in heart tissue from an aging mouse model. To investigate the role of sialic acid on Nav1.5 channel regulation, in vitro studies were conducted on HEK293 cells expressing Nav1.5 channels and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Treatment with a mix of sialidase enzymes was performed for monitoring Nav1.5 protein biosynthesis, trafficking, degradation, and recycling and patch clamp analysis was used to examine changes in sodium ion current. To investigate the impact of exogenous sialic acid production on Nav1.5 protein expression, cells were fed with modified mannosamine. Our results revealed a reduction in both α-2,3 and α-2,6 sialic acid levels in aged mice, which positively correlated with Nav1.5 protein levels. In vitro experiments demonstrated that decreased external sialic acid upon treatment induced Nav1.5 channel internalization and activated endocytic pathways, leading to proteasome-mediated degradation. Conversely, exogenous sialic acid restored Nav1.5 protein levels on the cell membrane. In conclusion, our findings suggest that age-related reductions in sialylation status in cardiac tissue induce Nav1.5 channel internalization. Modulating sialic acid levels could potentially serve as a promising therapeutic strategy to prevent cardiac dysfunction in the elderly population.