rs2253820 Variant Controls Blood Pressure Dip After Stroke by Increasing CLOCK-BMAL1 Expression

Area of Science:

• Neuroscience
• Cardiovascular Biology
• Genetics

Background:

• Circadian rhythm disturbances are linked to cardiovascular diseases, including stroke.
• The brain's central clock, regulated by circadian genes, governs daily rhythms.
• Understanding the interplay between circadian genes and blood pressure regulation is crucial for cardiovascular health.

Purpose of the Study:

• To investigate the interaction between the PER1 rs2253820 variant and blood pressure dip (BPD) status.
• To elucidate the underlying molecular mechanisms linking circadian rhythm disturbances to stroke severity.

Main Methods:

• Utilized spontaneously hypertensive rats with transient middle cerebral artery occlusion (SHR-tMCAO) models.
• Employed bioinformatics analysis to identify PER1 mutation sites.
• Validated findings using RT-qPCR, western blot, and immunohistochemistry.

Main Results:

• SHR-tMCAO models exhibited increased brain infarct volume correlated with circadian rhythm disturbances.
• The PER1 rs2253820 variant accelerated PER1 phosphorylation via CK1, leading to PER1 degradation.
• Knockdown of rs2253820 attenuated circadian rhythm disturbances, reduced PER1 phosphorylation, and inhibited BMAL1 and CLOCK transcription.

Conclusions:

• The PER1 rs2253820 variant exacerbates circadian rhythm disturbances and blood pressure dip, contributing to stroke severity.
• CK1-mediated PER1 phosphorylation plays a critical role in regulating circadian gene expression and neuronal damage.
• Targeting the PER1 rs2253820 variant or CK1 may represent a novel therapeutic approach for stroke and related cardiovascular conditions.