title: Cardiac melanocytes influence atrial reactive oxygen species involved with electrical and structural remodeling in mice.
abstract: Cardiac melanocyte-like cells (CMLCs) contribute to atrial arrhythmias when missing the melanin synthesis enzyme dopachrome tautomerase (Dct). While scavenging reactive oxygen species (ROS) in Dct-null mice partially suppressed atrial arrhythmias, it remains unclear if CMLCs influence atrial ROS and structure or if the electrical response of CMLCs to ROS differs from that of atrial myocytes. This study is designed to determine if CMLCs contribute to overall atrial oxidative stress or structural remodeling, and if ROS affects the electrophysiology of CMLCs differently than atrial myocytes. Immunohistochemical analysis showed higher expression of the oxidative marker 8-hydroxy-2'-deoxyguanosine in Dct-null atria versus Dct-heterozygous (Dct-het) atria. Exposing isolated CMLCs from Dct-het and Dct-null mice to hydrogen peroxide increased superoxide anion more in Dct-null CMLCs. Trichrome staining showed increased fibrosis in Dct-null atria, and treating Dct-null mice with the ROS scavenger Tempol reduced atrial fibrosis. Action potential recordings from atrial myocytes and isolated Dct-het and Dct-null CMLCs in response to hydrogen peroxide showed that the EC50 for action potential duration (APD) prolongation of Dct-null CMLCs was 8.2 ± 1.7 μmol/L versus 16.8 ± 2.0 μmol/L for Dct-het CMLCs, 19.9 ± 2.1 μmol/L for Dct-null atrial myocytes, and 20.5 ± 1.9 μmol/L for Dct-het atrial myocytes. However, APD90 was longer in CMLCs versus atrial myocytes in response to hydrogen peroxide. Hydrogen peroxide also induced more afterdepolarizations in CMLCs compared to atrial myocytes. These studies suggest that Dct within CMLCs contributes to atrial ROS balance and remodeling. ROS prolongs APD to a greater extent and induces afterdepolarizations more frequently in CMLCs than in atrial myocytes.
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hayoung
authors.initials: H
authors.lastname: Hwang
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Nataliya B
authors.initials: NB
authors.lastname: Petrenko
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jianhe
authors.initials: J
authors.lastname: Huang
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Schillinger
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania vickas.patel@temple.edu.
authors.forename: Vickas V
authors.initials: VV
authors.lastname: Patel
keywords: Afterdepolarizations; atrium; melanocyte‐like cells; mouse models; reactive oxygen species; remodeling