High glucose promotes atherosclerosis by regulating miRNA let7d-5p level

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Diabetes Complications

Background:

• Atherosclerosis (AS) is a common complication of diabetes.
• MicroRNA let-7d-5p (let7d-5p) expression is altered in diabetes-associated AS.
• The precise role of let7d-5p in AS pathogenesis remains unclear.

Purpose of the Study:

• To investigate the role of let7d-5p in diabetes-associated atherosclerosis.
• To elucidate the molecular mechanisms by which let7d-5p influences vascular smooth muscle cells (VSMCs).
• To explore the potential therapeutic effect of GLP-1 receptor agonists (GLP-1RA) on let7d-5p levels and AS.

Main Methods:

• Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to assess let7d-5p expression in human carotid plaques and VSMCs.
• In vitro gain- and loss-of-function studies to evaluate the impact of let7d-5p modulation on VSMC proliferation and migration.
• Mechanistic studies to identify the downstream targets and signaling pathways affected by let7d-5p, including the GSK3β/β-catenin pathway and HMGA2 mRNA.

Main Results:

• Lower let7d-5p expression was observed in carotid plaques from diabetic patients and in VSMCs under high glucose conditions.
• Overexpression of let7d-5p inhibited VSMC proliferation and migration, while inhibition of let7d-5p promoted these processes.
• let7d-5p was found to activate the GSK3β/β-catenin signaling pathway by targeting HMGA2 mRNA.
• Liraglutide, a GLP-1RA, increased let7d-5p levels, thereby inhibiting VSMC migration and proliferation.

Conclusions:

• High glucose promotes VSMC proliferation and migration via the let7d-5p/HMGA2/GSK3β/β-catenin pathway.
• Liraglutide may exert protective effects against atherosclerosis by upregulating let7d-5p levels.
• let7d-5p represents a potential therapeutic target for managing diabetes-associated atherosclerosis.