Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66^Shc

Area of Science:

• Cardiovascular Biology
• Metabolic Disorders
• Epigenetics

Background:

• Hyperglycaemia triggers reactive oxygen species (ROS), leading to cardiac dysfunction.
• Intensive glycaemic control (IGC) fails to prevent heart failure in diabetic patients, indicating unresolved mechanisms.

Purpose of the Study:

• Investigate the role of epigenetic regulation of p66^Shc in persistent myocardial dysfunction despite IGC.
• Elucidate the molecular pathways contributing to diabetic cardiomyopathy.

Main Methods:

• Assessed p66^Shc expression, oxidative stress, inflammation, and cardiac function in diabetic mice.
• Utilized gene silencing and echocardiography.
• Examined epigenetic modifications (demethylation, acetylation) on the p66^Shc promoter.
• Investigated the role of microRNAs (miRNAs) and chromatin-modifying enzymes (DNMT3b, SIRT1).

Main Results:

• Diabetic mice showed increased cardiac p66^Shc expression, oxidative stress, and dysfunction, unaffected by IGC.
• p66^Shc gene silencing restored cardiac function and reduced ROS.
• Dysregulation of DNMT3b/SIRT1, driven by miR-218 and miR-34a, caused persistent p66^Shc transcription.
• Inhibition of these miRNAs in human cardiomyocytes reversed epigenetic changes and reduced p66^Shc expression.

Conclusions:

• A complex epigenetic network involving miRNAs and chromatin modifiers drives p66^Shc transcription and ROS in diabetic cardiomyopathy.
• Pharmacological targeting of these epigenetic pathways holds promise for treating diabetic cardiomyopathy.