Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China.
Front Immunol. 2022 Aug 25;13:958677. doi: 10.3389/fimmu.2022.958677. eCollection 2022.
Genome-wide association studies (GWAS) have recently identified phosphatase and actin regulator-1 (PHACTR1) as a critical risk gene associated with polyvascular diseases. However, it remains largely unclear how PHACTR1 is involved in endothelial dysfunction. Here, by mining published datasets of human stable and vulnerable/ruptured plaque tissues, we observed upregulated expression of in vulnerable/ruptured plaques. Congruent with these data, we demonstrated increased gene expression in aortic endothelium from ApoE mice fed a western type diet compared with that in normal C57BL/6J mice. Relevantly, gene expression was upregulated by pro-inflammatory and pro-atherogenic stimuli, including TNF-α, IL-1β and oxidized LDL (oxLDL). By employing next-generation RNA sequencing, we demonstrate that PHACTR1 overexpression disrupts pathways associated with endothelial homeostasis. Cell biological studies unravel that PHACTR1 mediates endothelial inflammation and monocyte adhesion by activating NF-κB dependent intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) expression. In addition, overexpression of PHACTR1 also reduces the generation of nitric oxide (NO) by inhibiting Akt/eNOS activation. In-house compound screening of vasoprotective drugs identifies several drugs, including lipid-lowering statins, decreases PHACTR1 gene expression. However, PHACTR1 gene expression was not affected by another lipid-lowering drug-fenofibrate. We also performed a proteomic study to reveal PHACTR1 interacting proteins and validated that PHACTR1 can interact with heat shock protein A8 (HSPA8) which was reported to be associated with coronary artery disease and eNOS degradation. Further studies are warranted to confirm the precise mechanism of PHACTR1 in driving endothelial dysfunction. In conclusion, by using systems biology approach and molecular validation, we disclose the deleterious effects of PHACTR1 on endothelial function by inducing endothelial inflammation and reducing NO production, highlighting the potential to prevent endothelial dysfunction and atherosclerosis by targeting PHACTR1 expression. The precise role of endothelial cell PHACTR1 in polyvascular diseases remains to be validated in diseased conditions.
全基因组关联研究（GWAS）最近将磷酸酶和肌动蛋白调节剂-1（PHACTR1）鉴定为与多血管疾病相关的关键风险基因。然而，PHACTR1 如何参与内皮功能障碍在很大程度上仍不清楚。在这里，通过挖掘已发表的人类稳定和易损/破裂斑块组织数据集，我们观察到易损/破裂斑块中 PHACTR1 的表达上调。与这些数据一致，我们证明了喂食西式饮食的 ApoE 小鼠主动脉内皮中 PHACTR1 基因表达增加，而正常 C57BL/6J 小鼠则没有。相关地，促炎和促动脉粥样硬化刺激物，包括 TNF-α、IL-1β 和氧化 LDL（oxLDL），可上调 基因表达。通过采用下一代 RNA 测序，我们证明 PHACTR1 的过表达会破坏与内皮稳态相关的途径。细胞生物学研究表明，PHACTR1 通过激活 NF-κB 依赖性细胞间黏附分子 1（ICAM1）和血管细胞黏附分子 1（VCAM1）的表达来介导内皮炎症和单核细胞黏附。此外，PHACTR1 的过表达还通过抑制 Akt/eNOS 激活来减少一氧化氮（NO）的产生。血管保护药物的内部化合物筛选确定了几种药物，包括降脂他汀类药物，可降低 PHACTR1 基因表达。然而，另一种降脂药物——非诺贝特并不影响 PHACTR1 基因表达。我们还进行了蛋白质组学研究，以揭示 PHACTR1 相互作用蛋白，并验证了 PHACTR1 可以与热休克蛋白 A8（HSPA8）相互作用，HSPA8 被报道与冠心病和 eNOS 降解有关。需要进一步的研究来证实 PHACTR1 在驱动内皮功能障碍中的精确机制。总之，通过使用系统生物学方法和分子验证，我们揭示了 PHACTR1 通过诱导内皮炎症和减少 NO 产生对内皮功能的有害影响，强调了通过靶向 PHACTR1 表达来预防内皮功能障碍和动脉粥样硬化的潜力。内皮细胞 PHACTR1 在多血管疾病中的精确作用仍有待在疾病状态下验证。
