O-GlcNAcylation, oxidation and CaMKII contribute to atrial fibrillation in type 1 and type 2 diabetes by distinct mechanisms

Abstract

Diabetes mellitus and atrial fibrillation (AF) are major unsolved public health problems, and diabetes is an independent risk factor for AF in patients. However, the mechanism(s) underlying this clinical association is unknown. Elevated protein O-GlcNAcylation (OGN) and reactive oxygen species (ROS) are increased in diabetic hearts, and calmodulin kinase II (CaMKII) is a proarrhythmic signal that may be activated by OGN (OGN-CaMKII) and ROS (ox-CaMKII). We induced type 1 (T1D) and type 2 diabetes (T2D) in a portfolio of genetic mouse models capable of dissecting the role of OGN and ROS at CaMKII and the type 2 ryanodine receptor (RyR2), an intracellular Ca 2+ channel implicated as an important downstream mechanism of CaMKIImediated arrhythmias. Here we show that T1D and T2D significantly increased AF, similar to observations in patients, and this increase required CaMKII. While T1D and T2D both require ox-CaMKII, they respond differently to loss of OGN-CaMKII. Collectively, our data affirm CaMKII as a critical proarrhythmic signal in diabetic AF, and suggest ROS primarily promotes AF by ox-CaMKII, while OGN promotes AF by diverse mechanisms and targets, including RyR2. However, the proarrhythmic consequences of OGN-and ox-CaMKII differ between T1D and T2D. These results provide new and unanticipated insights into the mechanisms for increased AF in diabetes mellitus, and suggest successful future therapies will need to be different for AF in T1D and T2D.

Novel Biosensor Identifies Ruxolitinib as a Potent and Cardioprotective CaMKII Inhibitor

“…Thus, we are optimistic that CaMKII inhibition is feasible in humans using existing dosing. To demonstrate translational anti-arrhythmic potential we focused on atrial fibrillation, a common arrhythmia driven by CaMKII hyperactivity (58)(59)(60)(61)(62). In a validated model of hyperglycemia-induced atrial fibrillation, ruxolitinib displayed near complete rescue of the arrhythmic phenotype.…”

“…We chose atrial fibrillation as our focus since it is a major source of morbidity and mortality, affects nearly 50 million people worldwide globally, and is responsible for 20-30% of all ischemic stroke cases (56,57). CaMKII is a pivotal pro-arrhythmic signal in atrial fibrillation (58)(59)(60)(61)(62). We previously validated a mouse model of atrial fibrillation enhanced by diabetes, a major risk factor for atrial fibrillation in patients and known upstream activator of CaMKII (56,(62)(63)(64)(65).…”

“…CaMKII is a pivotal pro-arrhythmic signal in atrial fibrillation (58)(59)(60)(61)(62). We previously validated a mouse model of atrial fibrillation enhanced by diabetes, a major risk factor for atrial fibrillation in patients and known upstream activator of CaMKII (56,(62)(63)(64)(65). In this model, genetic and chemical interventions that reduced CaMKII activity suppressed atrial fibrillation in diabetic mice (62).…”

“…We previously validated a mouse model of atrial fibrillation enhanced by diabetes, a major risk factor for atrial fibrillation in patients and known upstream activator of CaMKII (56,(62)(63)(64)(65). In this model, genetic and chemical interventions that reduced CaMKII activity suppressed atrial fibrillation in diabetic mice (62). 10-minute systemic pretreatment with 75 mg/kg ruxolitinib in hyperglycemic mice abolished pacing-induced atrial fibrillation (Fig.…”

“…T1D Mouse Model: Type-1 diabetes (T1D) was induced as previously described (62), in adult (8 -12-week-old) male mice C57BL/6J mice (The Jackson Laboratory, ME, USA) by a single intraperitoneal (i.p.) injection of streptozotocin (STZ) (185mg/kg, Sigma-Aldrich) dissolved in a citrate buffer (citric acid and sodium citrate, pH 4.0) after a six hour fast.…”