Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure
Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y. Eugene Chen, Lin Chang
Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y. Eugene Chen, Lin Chang
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Research Article Vascular biology

Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure

Abstract

Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease. Thus, gaining insights into the molecular mechanisms of BP circadian variation is essential for comprehending BP regulation. Human genetic analyses suggest that PR domain–containing protein 16 (PRDM16), a transcription factor highly expressed in vascular smooth muscle cells (VSMCs), is significantly associated with BP-related traits. However, the roles of PRDM16 in BP regulation are largely unknown. Here, we demonstrate that BP in VSMC-specific Prdm16-KO (Prdm16SMKO) mice was significantly lower than that in control mice during the active period, resulting in aberrant BP circadian variation. Mesenteric artery rings from Prdm16SMKO mice showed a reduced response to phenylephrine. Mechanistically, we identified adrenergic receptor α 1d (Adra1d) as a transcriptional target of PRDM16. Notably, PRDM16 exhibited a remarkable circadian expression pattern and regulated the expression of clock genes, particularly Npas2, which is crucial for BP circadian variation regulation. Consequently, PRDM16 deficiency in VSMCs caused disrupted BP circadian variation through a reduced response to adrenergic signaling and clock gene regulation. Our findings provide insights into the intricate molecular pathways that govern circadian fluctuations in BP.

Authors

Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y. Eugene Chen, Lin Chang

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Figure 6

PRDM16 is involved in circadian rhythm regulation.

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PRDM16 is involved in circadian rhythm regulation. (A) Volcano plot of t...
(A) Volcano plot of the DEGs in thoracic aortas from Prdm16SMKO and control mice (n = 3). Upregulated DEGs are highlighted in red; downregulated DEGs are highlighted in blue. (B) The DEGs were analyzed for GO biological process (GO_BP) enrichment using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), and the top 10 significantly enriched terms are shown. Red bars and blue bars indicate GO_BP results from upregulated DEGs and downregulated DEGs, respectively. (C) Thoracic aortas from 10-week-old male C57/BL6J mice were harvested at 4-hour intervals over a 24-hour period. Prdm16 mRNA expression was determined by qPCR. ZT0 indicates lights on; ZT12 indicates lights off. n = 6 per time point. (D–G) The thoracic aortas from 10-week-old male Prdm16SMKO mice and control mice were harvested at 6-hour intervals over a 24-hour period. mRNA expression of canonical clock genes, including (D) Bmal1 and Npas2, (E) Cry1 and Cry2, and (F) Per1, Per2, and Per3, and the (G) PRDM16 transcriptional target gene Adra1d, were determined by qPCR. n = 5–6 per group per time point. Gray shadows in C–G indicate the nighttime. Data are presented as the mean ± SEM. P values were determined by 2-way ANOVA followed by Holm-Šidák multiple-comparison test.