Key result
D-galactose induces age-related sinoatrial node dysfunction via oxidative stress, ectopic PITX2 expression, and SHOX2 downregulation.
Why the study?
Age-related sinoatrial node dysfunction is increasing with population aging, but suitable animal modeling methods have been lacking.
Does D-galactose induce age-related sinoatrial node dysfunction in experimental mouse and cell models?
Does D-galactose induce age-related sinoatrial node dysfunction in experimental mouse and cell models?
D-galactose effectively models age-related sinoatrial node dysfunction, revealing that oxidative stress suppresses pacing-related ion channels via the PITX2/SHOX2 pathway.
D-galactose mouse model may aid mechanistic study of age-related SAN dysfunction; leaves open human relevance of PITX2/SHOX2 pathway.
With the population aging, age-related sinoatrial node dysfunction (SND) has been on the rise. Sinoatrial node (SAN) degeneration is an important factor for the age-related SND development. However, there is no suitable animal modeling method in this field. Here, we investigated whether D-galactose could induce SAN degeneration and explored the associated mechanism. In vivo, twelve C57BL/6 mice were divided into Control and D-galactose group to receive corresponding treatments. Senescence was confirmed by analyzing the hair and weight; cardiac function was evaluated through echocardiography, cerebral blood flux and serum-BNP; the SAN function was evaluated by electrocardiogram; fibrotic change was evaluated by Masson's trichrome staining and oxidative stress was assessed through DHE staining and serum indicators. Mechanism was verified through immunofluorescence-staining and Western blotting. In vitro, mouse-atrial-myocytes were treated with D-galactose, and edaravone was utilized as the ROS scavenger. Senescence, oxidative stress, proliferation ability and mechanism were verified through various methods, and intuitive evidence was obtained through electrophysiological assay. Finally, we concluded that D-galactose can be used to induce age-related SND, in which oxidative stress plays a key role, causing PITX2 ectopic expression and downregulates SHOX2 expression, then through the downstream GATA4/NKX2-5 axis, results in pacing-related ion channels dysfunction, and hence SND development.
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Zhang et al. (2023) studied Sinoatrial node dysfunction (n=12). D-galactose vs. Normal saline was evaluated on Sinoatrial node function and senescence (p=<0.05). D-galactose induced age-related sinoatrial node dysfunction via oxidative stress, causing PITX2 ectopic expression and downregulating SHOX2.
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