Decreased PLK2 promotes atrial fibrillation in diabetic mice through Nrf2/HO-1 pathway

Type 2 diabetes mellitus (T2DM) is associated with an increased incidence of atrial fibrillation (AF). However, the exact mechanisms involved have not yet been fully elucidated. Dysregulation of cardiac potassium channels can trigger AF. This study aimed to investigate the mechanisms of abnormal expression of atrial potassium channel proteins Kv1.5, Kv4.2, and Kv4.3 in type 2 diabetic mice.

The db/db mice and their control littermates were set as the T2DM group and the control (Con) group. Acetylcholine-calcium chloride was injected via the tail veins to induce AF. HL-1 cells were cultured with normal or high-glucose medium and treated with or without Dimethyl Fumarate (DMF) or hemin in vitro. The expression and cellular localization of proteins were evaluated by western blotting and immunofluorescence.

The results showed that high glucose impaired the expression of Kv1.5, Kv4.2 and Kv4.3 proteins both in vivo and in vitro, in parallel with a significant down-regulation of polo-like kinase 2 (PLK2), nuclear factor erythroid 2-related factor 2 (Nrf2), p-Nrf2 and heme oxygenase-1 (HO-1) proteins. Moreover, immunofluorescence revealed that both high glucose and PLK2 knockdown could result in reduced Nrf2 and p-Nrf2 expression and subsequent nuclear translocation. While overexpression of PLK2, treatment with DMF, an agonist of Nrf2, or hemin, an inducer of HO-1, could restore the reduction of Kv1.5, Kv4.2 and Kv4.3 proteins caused by high glucose.

Diabetes reduces the expression of Kv1.5, Kv4.2 and Kv4.3 proteins in atrial cells through inhibition of PLK2/Nrf2/HO-1 pathway, thereby leading to the increased susceptibility to AF in T2DM.