Endothelial cells (ECs) senescence is critical for vascular dysfunction, which leads to age-related disease. DHCR24, a 3β-hydroxysterol δ 24 reductase with multiple functions other than enzymatic activity, has been involved in age-related disease. However, little is known about the relationship between DHCR24 and vascular ECs senescence. We revealed that DHCR24 expression is chronologically decreased in senescent human umbilical vein endothelial cells (HUVECs) and the aortas of aged mice. ECs senescence in endothelium-specific DHCR24 knockout mice was characterized by increased P16 and senescence-associated secretory phenotype (SASP), decreased SIRT1 and cell proliferation, impaired endothelium-dependent relaxation, and elevated blood pressure. In vitro, DHCR24 knockdown in young HUVECs resulted in a similar senescence phenotype. DHCR24 deficiency impaired endothelial migration and tube formation and reduced nitric oxide (NO) levels. DHCR24 suppression also inhibited the caveolin-1/ERK signaling, probably responsible for increased reactive oxygen species (ROS) production and decreased eNOS/NO. Conversely, DHCR24 overexpression enhanced this signaling pathway, blunted the senescence phenotype, and improved cellular function in senescent cells, effectively blocked by the ERK inhibitor U0126. Moreover, desmosterol accumulation induced by DHCR24 deficiency promoted HUVECs senescence and inhibited caveolin-1/ERK signaling. Our findings demonstrate that DHCR24 is essential in ECs senescence.

中文翻译：

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DHCR24 不足通过抑制 Caveolin-1/ERK 信号传导促进血管内皮细胞衰老和内皮功能障碍

内皮细胞（EC）衰老对于血管功能障碍至关重要，从而导致与年龄相关的疾病。DHCR24 是一种 3β-羟基甾醇 δ 24 还原酶，具有酶活性以外的多种功能，与年龄相关疾病有关。然而，人们对 DHCR24 与血管内皮细胞衰老之间的关系知之甚少。我们发现，在衰老的人脐静脉内皮细胞 (HUVEC) 和老年小鼠的主动脉中，DHCR24 的表达按时间顺序降低。内皮特异性 DHCR24 敲除小鼠中 EC 衰老的特点是 P16 和衰老相关分泌表型 (SASP) 增加、SIRT1 和细胞增殖减少、内皮依赖性舒张受损以及血压升高。在体外，年轻 HUVEC 中的 DHCR24 敲低导致了类似的衰老表型。DHCR24 缺乏会损害内皮迁移和管形成，并降低一氧化氮 (NO) 水平。DHCR24 抑制还抑制 Caveolin-1/ERK 信号传导，这可能是导致活性氧 (ROS) 产生增加和 eNOS/NO 减少的原因。相反，DHCR24 过表达增强了这一信号通路，减弱了衰老表型，并改善了衰老细胞的细胞功能，并被 ERK 抑制剂 U0126 有效阻断。此外，DHCR24 缺陷引起的去氨甾醇积累促进 HUVEC 衰老并抑制 Caveolin-1/ERK 信号传导。我们的研究结果表明 DHCR24 在 EC 衰老中至关重要。