Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure
Zhenguo Wang, … , Y. Eugene Chen, Lin Chang
Zhenguo Wang, … , Y. Eugene Chen, Lin Chang
Published December 3, 2024
Citation Information: J Clin Invest. 2025;135(3):e183409. https://doi.org/10.1172/JCI183409.
View: Text | PDF
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

×

Figure 1

Predominant expression of PRDM16 in VSMCs and its gene-level associations with common variants.

Options: View larger image (or click on image) Download as PowerPoint
Predominant expression of PRDM16 in VSMCs and its gene-level association...
(A and B) Uniform manifold approximation and projection (UMAP) results showing higher expression of Prdm16 in smooth muscle cells (SMCs) compared with other cell populations in the aorta and artery by scRNA-Seq analysis of mouse aorta (GEO GSE193265, a total of 22,980 cells were included in this analysis) (A) and human carotid artery (GEO GSE155468 and GEO GSE155512 were integrated for analysis, a total of 15,685 cells were included in this analysis) (B). Fibro, fibroblasts; EC, endothelial cells; Mϕ, macrophages; NK, NK cells; B, B cells; T, T cells. (C) Circular plot shows gene-level phenotypic associations for PRDM16. Data were sourced from the Common Metabolic Diseases Knowledge Portal (https://t2d.hugeamp.org/gene.html?gene=PRDM16), focusing on the “Common Variants Association Table” and “HuGE Scores Table” for group categorization. The data ancestry includes African American or Afro-Caribbean, African unspecified, Asian, European, Greater Middle Eastern, Hispanic or Latin American, and Sub-Saharan African. After filtering out phenotypes with sample sizes of 100,000 or fewer and keeping the cardiometabolic disease–related traits, 59 phenotypes across 5 groups were obtained. The circular plot organizes groups alphabetically and phenotypes within each group by P value. The y axis represents –log10-transformed P values for standardized comparison. A generally accepted threshold for significance of MAGMA results is P ≤ 2.5 × 10–6 (dashed red circle). The blue color represents the sample size. MI, myocardial infarction; MAP, mean arterial pressure; HF, heart failure; CRP, plasma C-reactive protein; CADinNonT2D, coronary artery disease in individuals without type 2 diabetes; CK, creatine kinase; HR, heart rate; BS, random glucose; HBA1C, hemoglobin A1C; BSandFG, random and fasting glucose; FG, fasting glucose; BSadjFastingTime, random glucose adj fasting time; T2DadjBMI, type 2 diabetes adj BMI; FGadjBMI, fasting glucose adj BMI; T2D, type 2 diabetes; FIadjBMI, fasting insulin adj BMI; HBA1CadjBMI, HBA1C adj BMI; FI, fasting insulin; CHOL, total cholesterol; nonHDL, non-HDL cholesterol; TG, triglycerides; ApoA, serum apolipoprotein A; ApoB, serum apolipoprotein B; TGnonT2D, triglyceride levels in individuals without type 2 diabetes; TGtoHDL, triglyceride-to-HDL ratio; Urage, serum urate; NaExcretion, urinary sodium excretion; UA, urinary albumin; eGFRcreat, serum creatinine; UPCR, urinary potassium-to-creatinine ratio; eGFRcreateNoDiabetes, eGFRcreat in individuals without diabetes; USPR, urinary sodium-to-potassium ratio; eGFRcreateInDiabetes, eGFRcreat in individuals with diabetes; eGFRcreat_med_DeclineAdjDM, eGFRcreat median annual decline adj diabetes status; eGFRcreat_med_DeclineAdjBL, eGFRcreat median annual decline adj baseline; KExcretion, urinary potassium excretion; UACR, urinary albumin-to-creatinine ratio; BUN, blood urea nitrogen; USCR, urinary sodium-to-creatinine ratio; eGFRcys, serum cystatin C; eGFRcreatRapid3, eGFRcreat decline, Rapid3 definition; CKD, chronic kidney disease; toastSAO, toast small artery occlusion; toastLAA, toast large artery atherosclerosis; toastCE, toast cardio-aortic embolism.