SIRT6 Mitigates Heart Failure With Preserved Ejection Fraction in Diabetes

Area of Science:

• Cardiovascular Biology
• Metabolic Disease Research
• Molecular Mechanisms of Heart Failure

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a growing clinical challenge, particularly in diabetic patients.
• The underlying mechanisms linking diabetes to HFpEF remain poorly understood.
• Endothelial dysfunction is implicated in HFpEF pathophysiology.

Purpose of the Study:

• To investigate the role of sirtuin 6 (SIRT6) in regulating endothelial fatty acid transport in the context of diabetic HFpEF.
• To explore SIRT6 as a potential therapeutic target for diabetic HFpEF.

Main Methods:

• Utilized echocardiography, hemodynamics, RNA-sequencing, and molecular biology techniques.
• Developed diabetic HFpEF mouse models and humanized SIRT6 transgenic mice.
• Conducted in vitro and in vivo gain- and loss-of-function studies of SIRT6.

Main Results:

• Endothelial SIRT6 expression was significantly reduced in diabetic HFpEF cardiac tissues.
• Genetic restoration of endothelial SIRT6 in diabetic mice ameliorated diastolic dysfunction and reduced cardiac lipid accumulation.
• SIRT6 was found to downregulate endothelial fatty acid uptake by suppressing PPARγ expression via histone deacetylation.
• Pharmacological activation of SIRT6 with MDL-800 in diabetic mice improved cardiac function and metabolism.

Conclusions:

• Impaired endothelial SIRT6 expression is a key link between diabetes and HFpEF, mediated by altered fatty acid transport.
• Restoring endothelial SIRT6 function offers a promising therapeutic strategy for diabetic HFpEF.
• Further clinical evaluation of SIRT6-targeting therapies is warranted.