Liraglutide protects high-glucose-stimulated fibroblasts by activating the CD36-JNK-AP1 pathway to downregulate P4HA1

Area of Science:

• Cardiovascular Biology
• Endocrinology
• Molecular Medicine

Background:

• Diabetic cardiomyopathy (DCM) is a severe diabetes mellitus complication.
• Glucagon-like peptide-1 (GLP-1) and prolyl 4-hydroxylase subunit alpha-1 (P4HA1) impact cardiovascular function.
• The interaction between GLP-1 and P4HA1 in cardiac fibroblasts (CFs) requires further elucidation.

Purpose of the Study:

• To investigate the molecular mechanisms of liraglutide in high-glucose (HG)-induced cardiac fibroblasts (CFs).
• To explore the role of prolyl 4-hydroxylase subunit alpha-1 (P4HA1) in HG-mediated cardiac fibrosis.
• To elucidate the signaling pathway involving liraglutide, P4HA1, CD36, JNK, and AP-1.

Main Methods:

• Quantitative real-time PCR (qRT-PCR) and Western blotting.
• Cell Counting Kit-8 (CCK-8), EdU, flow cytometry, wound healing, and Transwell assays.
• Gene silencing of P4HA1 and inhibition of CD36 or JNK signaling.

Main Results:

• High glucose promoted CF proliferation and cardiac fibrosis.
• Liraglutide and P4HA1 silencing inhibited HG-induced CF proliferation, migration, and invasion, while promoting cell cycle arrest and apoptosis.
• Liraglutide downregulated P4HA1, upregulated CD36 and P-JNK, and enhanced AP-1 DNA binding activity; CD36 or JNK inhibition increased P4HA1 expression.

Conclusions:

• Liraglutide may reduce myocardial fibrosis by downregulating P4HA1 expression through the CD36-JNK-AP1 pathway.
• This study offers novel insights into the molecular mechanisms of liraglutide in HG-mediated CFs.
• Findings highlight potential therapeutic targets for diabetic cardiomyopathy.