It is recognized that stress can induce cardiac dysfunction, but the underlying mechanisms are not well understood. The present study aimed to test the hypothesis that chronic negative stress leads to alterations in DNA methylation of certain cardiac genes, which in turn contribute to pathologic remodeling of the heart. We found that mice that were exposed to chronic restraint stress (CRS) for 4 wk exhibited cardiac remodeling toward heart failure, as characterized by ventricular chamber dilatation, wall thinning, and decreased contractility. CRS also induced cardiac arrhythmias, including intermittent sinus tachycardia and bradycardia, frequent premature ventricular contraction, and sporadic atrioventricular conduction block. Circulating levels of stress hormones were elevated, and the cardiac expression of tyrosine hydroxylase, a marker of sympathetic innervation, was increased in CRS mice. Using reduced representation bisulfite sequencing, we found that although CRS did not lead to global changes in DNA methylation in the murine heart, it nevertheless altered methylation at specific genes that are associated with the dilated cardiomyopathy (DCM) (e.g., desmin) and adrenergic signaling of cardiomyocytes (ASPC) (e.g., adrenergic receptor‐α1) pathways. We conclude that CRS induces cardiac remodeling and arrhythmias, potentially through altered methylation of myocardial genes associated with the DCM and ASPC pathways.—Zhang P., Li, T., Liu, Y.‐Q., Zhang, H., Xue, S.‐M., Li, G., Cheng, H.‐Y.M., Cao, J.‐M. Contribution of DNA methylation in chronic stress‐induced cardiac remodeling and arrhythmias in mice. FASEB J. 33, 12240‐12252 (2019). http://www.fasebj.org

Background: The toxicity of silica nanoparticles (SiNPs) on cardiac electrophysiology has seldom been evaluated. Methods: Patch-clamp was used to investigate the acute effects of SiNP-100 (100 nm) and SiNP-20 (20 nm) on the transmembrane potentials (TMPs) and ion channels in cultured neonatal mouse ventricular myocytes. Calcium mobilization in vitro, cardiomyocyte ROS generation, and LDH leakage after exposure to SiNPs in vitro and in vivo were measured using a microplate reader. Surface electrocardiograms were recorded in adult mice to evaluate the arrhythmogenic effects of SiNPs in vivo. SiNP endocytosis was observed using transmission electron microscopy. Results: Within 30 min, both SiNPs (10 −8-10 −6 g/mL) did not affect the resting potential and I K1 channels. SiNP-100 increased the action potential amplitude (APA) and the I Na current density, but SiNP-20 decreased APA and I Na density. SiNP-100 prolonged the action potential duration (APD) and decreased the I to current density, while SiNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased I to density. Both SiNPs (10 −6 g/mL) induced calcium mobilization but did not increase ROS and LDH levels and were not endocytosed within 10 min in cardiomyocytes in vitro. In vivo, SiNP-100 (4-10 mg/kg) and SiNP-20 (4-30 mg/kg) did not elevate myocardial ROS but increased LDH levels depending on dose and exposure time. The same higher dose of SiNPs (intravenously injected) induced tachyarrhythmias and lethal bradyarrhythmias within 90 min in adult mice. Conclusion: SiNPs (i) exert rapid toxic effects on the TMPs of cardiomyocytes in vitro largely owing to their direct interfering effects on the I Na and I to channels and Ca 2+ homeostasis but not I K1 channels and ROS levels, and (ii) induce tachyarrhythmias and lethal bradyarrhythmias in vivo. SiNP-100 is more toxic than SiNP-20 on cardiac electrophysiology, and the toxicity mechanism is likely more complicated in vivo.