Cardiac overexpression of perilipin 2 induces atrial steatosis, connexin 43 remodeling, and atrial fibrillation in aged mice

Abstract

Atrial fibrillation (AF) is prevalent in patients with obesity and diabetes, and such patients often exhibit cardiac steatosis. Since the role of cardiac steatosis per se in the induction of AF has not been elucidated, the present study was designed to explore the relation between cardiac steatosis and AF. Transgenic (Tg) mice with cardiac-specific overexpression of perilipin 2 (PLIN2) were housed in the laboratory for more than 12 mo before the study. Electron microscopy of the atria of PLIN2-Tg mice showed accumulation of small lipid droplets around mitochondrial chains, and five- to ninefold greater atrial triacylglycerol (TAG) content compared with wild-type (WT) mice. Electrocardiography showed significantly longer RR intervals in PLIN2-Tg mice than in WT mice. Transesophageal electrical burst pacing resulted in significantly higher prevalence of sustained (>5 min) AF (69%) in PLIN2-Tg mice than in WT mice (24%), although it was comparable in younger (4-mo-old) mice. Connexin 43 (Cx43), a gap junction protein, was localized at the intercalated disks in WT atria but was heterogeneously distributed on the lateral side of cardiomyocytes in PLIN2-Tg atria. Langendorff-perfused hearts using the optical mapping technique showed slower and heterogeneous impulse propagation in PLIN2-Tg atria compared with WT atria. Cardiac overexpression of hormone-sensitive lipase in PLIN2-Tg mice resulted in atrial TAG depletion and amelioration of AF susceptibility. The results suggest that PLIN2-induced steatosis is associated with Cx43 remodeling, impaired conduction propagation, and higher incidence of AF in aged mice. Therapies targeting cardiac steatosis could be potentially beneficial against AF in patients with obesity or diabetes.

Updates on epicardial adipose tissue mechanisms on atrial fibrillation

“…Calcium channel protein levels and related miRNAs were regulated in older patients, suggesting their function with aging in AF occurrence 102 . Perilipin 2, a lipid droplet protein, was recently demonstrated to contribute to the lateralization of connexin 43 (Cx43), evoking conduction slowing, which could explain the AF vulnerability of aged perilipin 2‐transgenic mice 103 . Because perilipin is one of the main proteins involved in lipid accumulation in adipocytes, these results suggest the role of local fat in Cx43 lateralization in AF cardiomyocytes.…”

New Insights on the Role of Connexins and Gap Junctions Channels in Adipose Tissue and Obesity

“…Based on the relationship between adipose tissue components and the presence of AF, various groups have investigated specific factors that regulate atrial electrical remodeling, and the associations between adipose tissue and regulation of Cx43 expression and/or activity during AF [119,120].…”

“…More recently, Sato et al [120] studied the relationship between cardiac steatosis and AF in mice overexpressing Perilipin 2 (PLIN2). In their study, transgenic mice showed increased atrial fat accumulation and electrocardiographic abnormalities, with a higher prevalence of persistent AF.…”

Lipid Droplet-Associated Proteins in Cardiomyopathy

“…PLIN2-induced LDs were sensitive to lipolytic stimuli after fasting, and hence, the accumulation of LDs would be reduced despite the high concentrations of FFA in the circulating plasma [97]. Cardiac-specific expression of PLIN2 resulted in slower conduction propagation and induced a higher incidence of atrial fibrillation in aged mice [99].…”