School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China.
Cells. 2023 May 16;12(10):1401. doi: 10.3390/cells12101401.
Hypoxia-induced vascular endothelial dysfunction (VED) is a significant contributor to several severe human diseases, including heart disease, stroke, dementia, and cancer. However, current treatment options for VED are limited due to the lack of understanding of the underlying disease mechanisms and therapeutic leads. We recently discovered a heat-stable microprotein in ginseng, called ginsentide TP1, that has been shown to reduce vascular dysfunction in cardiovascular disease models. In this study, we use a combination of functional assays and quantitative pulsed SILAC proteomics to identify new proteins synthesized in hypoxia and to show that ginsentide TP1 provides protection for human endothelial cells against hypoxia and ER stress. Consistent with the reported findings, we also found that hypoxia activates various pathways related to endothelium activation and monocyte adhesion, which in turn, impairs nitric oxide (NO) synthase activity, reduces the bioavailability of NO, and increases the production of reactive oxygen species that contribute to VED. Additionally, hypoxia triggers endoplasmic reticulum stress and initiates apoptotic signaling pathways associated with cardiovascular pathology. Treatment with ginsentide TP1 reduced surface adhesion molecule expression, prevented activation of the endothelium and leukocyte adhesion, restored protein hemostasis, and reduced ER stress to protect against hypoxia-induced cell death. Ginsentide TP1 also restored NO signaling and bioavailability, reduced oxidative stress, and protected endothelial cells from endothelium dysfunction. In conclusion, this study shows that the molecular pathogenesis of VED induced by hypoxia can be mitigated by treatment with ginsentide TP1, which could be one of the key bioactive compounds responsible for the "cure-all" effect of ginseng. This research may lead to the development of new therapies for cardiovascular disorders.
缺氧诱导的血管内皮功能障碍 (VED) 是几种严重人类疾病的重要原因，包括心脏病、中风、痴呆和癌症。然而，由于对潜在疾病机制和治疗靶点的了解有限，目前针对 VED 的治疗选择有限。我们最近在人参中发现了一种热稳定的微蛋白，称为 Ginsentide TP1，它已被证明可减少心血管疾病模型中的血管功能障碍。在这项研究中，我们使用功能测定和定量脉冲 SILAC 蛋白质组学相结合的方法来鉴定在缺氧条件下合成的新蛋白，并表明 Ginsentide TP1 可为人内皮细胞提供针对缺氧和内质网应激的保护。与报道的发现一致，我们还发现缺氧激活了与内皮细胞激活和单核细胞黏附相关的各种途径，这反过来又会损害一氧化氮 (NO) 合酶的活性，降低 NO 的生物利用度，并增加活性氧的产生，从而导致 VED。此外，缺氧会引发内质网应激并启动与心血管病理学相关的凋亡信号通路。用 Ginsentide TP1 处理可减少表面黏附分子的表达，防止内皮细胞和白细胞的激活和黏附，恢复蛋白质的止血作用，并减轻内质网应激以防止缺氧诱导的细胞死亡。Ginsentide TP1 还可恢复 NO 信号和生物利用度，减少氧化应激，并保护内皮细胞免受内皮功能障碍的影响。总之，这项研究表明，Ginsentide TP1 治疗可减轻由缺氧引起的 VED 的分子发病机制，它可能是人参“治百病”效应的关键生物活性化合物之一。这项研究可能为心血管疾病的治疗方法的发展提供新的途径。
