Title
Decreased bioavailability of hydrogen sulfide links vascular endothelium and atrial remodeling in atrial fibrillation
Document Type
Article
Publication Date
1-1-2021
Abstract
Oxidative stress drives the pathogenesis of atrial fibrillation (AF), the most common arrhythmia. In the cardiovascular system, cystathionine γ-lyase (CSE) serves as the primary enzyme producing hydrogen sulfide (HS), a mammalian gasotransmitter that reduces oxidative stress. Using a case control study design in patients with and without AF and a mouse model of CSE knockout (CSE-KO), we evaluated the role of HS in the etiology of AF. Patients with AF (n = 51) had significantly reduced plasma acid labile sulfide levels compared to patients without AF (n = 65). In addition, patients with persistent AF (n = 25) showed lower plasma free sulfide levels compared to patients with paroxysmal AF (n = 26). Consistent with an important role for HS in AF, CSE-KO mice had decreased atrial sulfide levels, increased atrial superoxide levels, and enhanced propensity for induced persistent AF compared to wild type (WT) mice. Rescuing HS signaling in CSE-KO mice by Diallyl trisulfide (DATS) supplementation or reconstitution with endothelial cell specific CSE over-expression significantly reduced atrial superoxide, increased sulfide levels, and lowered AF inducibility. Lastly, low HS levels in CSE KO mice was associated with atrial electrical remodeling including longer effective refractory periods, slower conduction velocity, increased myocyte calcium sparks, and increased myocyte action potential duration that were reversed by DATS supplementation or endothelial CSE overexpression. Our findings demonstrate an important role of CSE and HS bioavailability in regulating electrical remodeling and susceptibility to AF.
Publication Source (Journal or Book title)
Redox biology
First Page
101817
Recommended Citation
Watts, M., Kolluru, G. K., Dherange, P., Pardue, S., Si, M., Shen, X., Trosclair, K., Glawe, J., Al-Yafeai, Z., Iqbal, M., Pearson, B. H., Hamilton, K. A., Orr, A. W., Glasscock, E., Kevil, C. G., & Dominic, P. (2021). Decreased bioavailability of hydrogen sulfide links vascular endothelium and atrial remodeling in atrial fibrillation. Redox biology, 38, 101817. https://doi.org/10.1016/j.redox.2020.101817