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 5

PRDM16 is essential for VSMC contractility.

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PRDM16 is essential for VSMC contractility. (A–C) Primary VSMCs isolated...
(A–C) Primary VSMCs isolated from rat thoracic aortas were infected with lentivirus carrying shRNA (A and C) or transfected with control siRNA (siCtrl) (10 nM) or siPrdm16 (10 nM) (B) for 48 hours. Cells with stable shRNA expression were selected by puromycin. (A) Representative images of the collagen-based contraction assay and quantitative analysis. n = 4. Scale bars: 0.5 cm. (B) Relative expression levels of contractile genes were determined by qPCR. n = 3. (C) Relative protein expression levels were determined by Western blotting; representative gels are shown. n = 6. (D) Representative image of collagen-based contraction assay of cultured VSMCs isolated from rat mesenteric arteries upon Prdm16 KD by shRNA. n = 3. Scale bars: 0.5 cm. (E) Relative protein expression levels in cultured VSMCs isolated from rat mesenteric arteries were determined by Western blotting upon Prdm16 KD by shRNA. n = 3. (F) Expression of contractile markers in the medial layer of thoracic aorta were determined by Western blotting. n = 5. Data are presented as the mean ± SEM. P values were determined by 2-tailed Student’s t test.