Bmal1 Regulates Vascular Calcification via Noncanonical Circadian Pathway-Brief Report

Area of Science:

• Cardiovascular Biology
• Endocrinology
• Circadian Rhythms

Background:

• Vascular calcification is a significant cause of cardiovascular complications in diabetes.
• Diabetes disrupts circadian rhythms, but the role of circadian regulators in vascular calcification is unclear.
• Vascular smooth muscle cell (SMC) osteogenic reprogramming contributes to vascular calcification.

Purpose of the Study:

• To investigate the role of the core circadian protein Bmal1 in diabetes-associated vascular calcification.
• To elucidate the molecular mechanisms by which Bmal1 influences vascular calcification in diabetes.

Main Methods:

• Examined Bmal1 expression in diabetic mouse aortas, human diabetic arteries, and high-glucose-exposed SMCs.
• Generated SMC-specific Bmal1 knockout mice and induced diabetes.
• Assessed vascular calcification and stiffness using calcium staining and pulse wave velocity.
• Utilized RNA sequencing, ChIP, and CRISPR-Cas9 to define Bmal1 regulatory mechanisms.

Main Results:

• Bmal1 was selectively upregulated in diabetic arteries and SMCs under hyperglycemia.
• SMC-specific Bmal1 deletion attenuated diabetes-induced vascular calcification and aortic stiffness.
• Bmal1 directly binds to the Runx2 promoter, enhancing its transcription via a noncanonical circadian pathway.

Conclusions:

• Bmal1 is a key mediator of diabetes-induced vascular calcification through direct transcriptional regulation of Runx2.
• This study reveals a novel pathogenic role for Bmal1 in vascular disease.
• Targeting dysregulated circadian factors like Bmal1 may offer new therapeutic avenues for diabetic vascular complications.