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

Circadian rhythm (CR) disturbances are associated with the development of cardiovascular diseases, including stroke. The central clock in the brain, which is maintained by circadian genes, maintains the daily rhythm according to the external environment. Here, we aimed to probe the interaction between the PER1rs2253820 variant and blood pressure dip (BPD) status and mechanisms. We studied spontaneously hypertensive rats (SHR) with transient middle cerebral artery occlusion (SHR-tMCAO). The mutation site of PER1 was identified using bioinformatics analysis, followed by RT-qPCR and western blot validation. SHR-tMCAO showed increased brain infarct volume associated with CR. CK1, BMAL1, and CLOCK proteins oscillated synchronously in SHR-tMCAO, whereas PER1 showed rhythm disturbances. CK1, CLOCK, and BMAL1 levels first elevated and then slowly decreased after ischemia, whereas PER1 level continued to decrease. CLOCK and PER1 are co-localized in the suprachiasmatic nucleus of the hypothalamus. rs2253820 accelerates PER1 phosphorylation via CK1. The rs2253820 knockdown attenuated CR disturbances, reduced PER1 phosphorylation in SHR and inhibited the transcription of BMAL1 and CLOCK. CK1 suppression attenuated the degradation of PER1 phosphorylation and reduced neuronal damage. Overall, rs2253820 accelerated PER1v phosphorylation via CK1, leading to PER1 degradation, BMAL1 and CLOCK1 transcription, and BPD exacerbation.