Decreased bioavailability of hydrogen sulfide links vascular endothelium and atrial remodeling in atrial fibrillation
| Autor: | A. Wayne Orr, Kathryn A. Hamilton, Xinggui Shen, John D. Glawe, Brenna H. Pearson, Paari Dominic, Megan N. Watts, Christopher G. Kevil, Zaki Al-Yafeai, Mazen Iqbal, Sibile Pardue, Krystle Trosclair, Parinita Dherange, Edward Glasscock, Gopi K. Kolluru, Man Si |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Clinical Biochemistry Biological Availability medicine.disease_cause Biochemistry Pathogenesis 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Internal medicine parasitic diseases medicine Myocyte Animals Humans lcsh:QH301-705.5 Mice Knockout lcsh:R5-920 biology Hydrogen sulfide Superoxide business.industry Organic Chemistry Atrial fibrillation Endothelial function Atrial Remodeling medicine.disease Cystathionine beta synthase Electrical remodeling Endothelial stem cell 030104 developmental biology Diallyl trisulfide Endocrinology chemistry lcsh:Biology (General) Oxidative stress Case-Control Studies biology.protein Endothelium Vascular business lcsh:Medicine (General) 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Redox Biology, Vol 38, Iss, Pp 101817-(2021) Redox Biology |
| ISSN: | 2213-2317 |
| Popis: | 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 (H2S), 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 H2S 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 H2S 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 H2S 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 H2S 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 H2S bioavailability in regulating electrical remodeling and susceptibility to AF. Graphical abstract Central Illustration Figure: 116 patients with (n = 51) and without atrial fibrillation (AF) (n = 65) had plasma sulfide pools measured in the base control human study (left). Patients with AF had significantly reduced acid labile sulfide. Paroxysmal AF patients (n = 26) had significantly lower free sulfide compared to patients with persistent AF (n = 25). Patients who had rhythm conversion had increase in free sulfide but not acid labile sulfide at 30 days follow up. Cystathionine ϒ-lyase knock out mice (CSE-KO) has reduced atrial sulfide levels, increased reactive oxygen species (ROS), longer atrial effective refractory period (AERP), longer action potential duration (APD) of atrial myocytes, slower conduction velocity, increased calcium sparks and increased AF inducibility and duration. Sulfide supplementation by retro-orbital diallyl tri-sulfide (DATS) or by endothelial overexpression of CSE reversed these changes in CSE-KO mice.Image 1 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|