Abstract Body: Disruption of circadian rhythms is a significant risk factor for cardiovascular diseases, yet the underlying mechanisms remain incompletely elucidated. BMAL1, a core component of the circadian clock, is critical for regulating metabolic and vascular homeostasis. This study investigates the role of BMAL1 in perivascular adipose tissue (PVAT) in atherosclerotic development and underlying mechanisms.

To evaluate the impact of BMAL1 deficiency, we utilized BA-Bmal1 knockout (KO) and wild-type control mice, as well as ApoE/BA-Bmal1 double-knockout (DKO) and ApoE KO control mice. All animals were maintained on a chow diet, the PVAT from the thoracic aorta (TA-PVAT) and abdominal aorta (AA-PVAT) were harvested at Zeitgeber Time 2-3. Histological assessments were performed to evaluate lipid droplet morphology, and transcriptomic analyses were used to identify differentially expressed genes (DEGs). Key metabolic pathways and regulators were further validated.

ApoE/BA-Bmal1 DKO mice exhibited exacerbated atherosclerosis, as evidenced by increased aortic plaque burden and histological abnormalities. Transcriptomic analysis of TA-PVAT revealed upregulation of glycolytic and lipogenic gene expression, indicating metabolic reprogramming in the absence of BMAL1. Histological analyse showed BA-Bmal1 KO mice has larger lipid droplets in both TA-PVAT and AA-PVAT, consistent with dysregulated lipid metabolism. Furthermore, the expression of carbohydrate response element-binding protein (ChREBP), a master regulator of lipogenesis, was significantly elevated in the PVAT of BA-Bmal1-KO mice.

In conclusion, BMAL1 deficiency in PVAT exacerbates atherosclerosis by promoting metabolic dysregulation and lipid accumulation in PVAT. These findings underscore the importance of circadian regulation in adipose tissue for vascular health and highlight BMAL1 as a potential therapeutic target for atherosclerosis management.