Advanced glycation end products induce senescence of atrial myocytes and increase susceptibility of atrial fibrillation in diabetic mice

Abstract

Diabetes mellitus (DM) is a common chronic metabolic disease caused by significant accumulation of advanced glycation end products (AGEs). Atrial fibrillation (AF) is a common cardiovascular complication of DM. Here, we aim to clarify the role and mechanism of atrial myocyte senescence in the susceptibility of AF in diabetes. Rapid transesophageal atrial pacing was used to monitor the susceptibility of mice to AF. Whole‐cell patch‐clamp was employed to record the action potential (AP) and ion channels in single HL‐1 cell and mouse atrial myocytes. More importantly, anti‐RAGE antibody and RAGE‐siRNA AAV9 were used to investigate the relationship among diabetes, aging, and AF. The results showed that elevated levels of p16 and retinoblastoma (Rb) protein in the atrium were associated with increased susceptibility to AF in diabetic mice. Mechanistically, AGEs increased p16/Rb protein expression and the number of SA‐β‐gal‐positive cells, prolonged the action potential duration (APD), reduced protein levels of Cav1.2, Kv1.5, and current density of ICa,L, IKur in HL‐1 cells. Anti‐RAGE antibody or RAGE‐siRNA AAV9 reversed these effects in vitro and in vivo, respectively. Furthermore, downregulating p16 or Rb by siRNA prevented AGEs‐mediated reduction of Cav1.2 and Kv1.5 proteins expression. In conclusion, AGEs accelerated atrial electrical remodeling and cellular senescence, contributing to increased AF susceptibility by activating the p16/Rb pathway. Inhibition of RAGE or the p16/Rb pathway may be a potential therapeutic target for AF in diabetes.

Resveratrol Alleviates Advanced Glycation End-Products-Related Renal Dysfunction in D-Galactose-Induced Aging Mice

“…When telomeres shorten and become inactive, cells interpret this as a break in the DNA strand and respond by activating the p53/p21 CIP1/WAF1 pathway, causing cell-cycle arrest and inducing replicative senescence [ 26 , 28 ]. AGEs can induce cellular senescence in endothelial cells [ 29 ] and atrial myocytes [ 30 ]. Resveratrol has been shown to prevent high-glucose-induced cellular senescence in cultured human diploid fibroblasts [ 31 ].…”

Effect of physical activity on incident atrial fibrillation in individuals with varying duration of diabetes: a nationwide population study

“…The increased incidence of AF in individuals with diabetes may be attributed to factors such as left atrial enlargement, interstitial fibrosis in the atrial myocardium, and electrical remodeling [ 38 , 39 ]. Moreover, findings from an in vitro study found a potential link between advanced glycation end products and heightened atrial myocyte senescence, contributing to a susceptibility to AF [ 40 ].…”

Identification of hub genes and pathways associated with cellular senescence in diabetic foot ulcers via comprehensive transcriptome analysis

“…Thus, senescent cells may be a major cause and consequence of tissue damage and abnormal metabolic changes, central to the pathogenic circuit of diabetes 8 . The diabetic microenvironment also promotes CS 9 . Recent studies have shown that hyperinsulinemia leads to a premature senescent transcriptomic and secretory profile in mature adipocytes, 10 while also causing insulin resistance in neurons, which results in a senescence‐like phenotype 11 .…”

“… 8 The diabetic microenvironment also promotes CS. 9 Recent studies have shown that hyperinsulinemia leads to a premature senescent transcriptomic and secretory profile in mature adipocytes, 10 while also causing insulin resistance in neurons, which results in a senescence‐like phenotype. 11 Additionally, recent research indicates that sustained hyperinsulinemia contributes to the senescence of hepatocytes.…”