Centre for Translational Bone, Joint and Soft Tissue Research, Medical Faculty and University Centre for Orthopaedics and Trauma Surgery, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, Germany; Department of Pharmacy, the First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, China.
Centre for Translational Bone, Joint and Soft Tissue Research, Medical Faculty and University Centre for Orthopaedics and Trauma Surgery, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, Germany.
Biochem Pharmacol. 2014 Jul 1;90(1):34-49. doi: 10.1016/j.bcp.2014.04.008. Epub 2014 Apr 26.
The vascular endothelium is specifically sensitive to oxidative stress, and this is one of the mechanisms that causes widespread endothelial dysfunction in most cardiovascular diseases and disorders. Protection against reactive oxygen species (ROS)-mediated oxidative damage via antioxidant mechanisms is essential for tissue maintenance and shows therapeutic potential for patients suffering from cardiovascular and metabolic disorders. Salvianolic acid B (SalB), a natural bioactive component known from Traditional Chinese Medicine, has been reported to exert cellular protection in various types of cells. However, the underlying mechanisms involved are not fully understood. Here, we showed that SalB significantly promoted the migratory and tube formation abilities of human bone marrow derived-endothelial progenitor cells (BM-EPCs) in vitro, and substantially abrogated hydrogen peroxide (H2O2)-induced cell damage. SalB down-regulated Nox4 and eNOS, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression upon H2O2 induction that in turn prevents oxidative-induced endothelial dysfunction. Moreover, SalB suppressed the Bax/Bcl-xL ratio and caspase-3 activation after H2O2 induction. Furthermore, our results provide mechanistic evidence that activation of the mTOR/p70S6K/4EBP1 pathways is required for both SalB-mediated angiogenic and protective effects against oxidative stress-induced cell injury in BM-EPCs. Suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways by SalB significantly protected BM-EPCs against cell injury caused by oxidative stress via reduction of intracellular ROS levels and apoptosis. Taken together, by providing a mechanistic insight into the modulation of redox states in BM-EPCs by SalB, we suggest that SalB has a strong potential of being a new proangiogenic and cytoprotective therapeutic agent with applications in the field of endothelial injury-mediated vascular diseases.
血管内皮细胞对氧化应激特别敏感，这是大多数心血管疾病和紊乱中广泛内皮功能障碍的机制之一。通过抗氧化机制防止活性氧（ROS）介导的氧化损伤对于组织维持至关重要，并显示出对患有心血管和代谢紊乱的患者的治疗潜力。丹酚酸 B（SalB）是一种来自中药的天然生物活性成分，已被报道在各种类型的细胞中发挥细胞保护作用。然而，其涉及的潜在机制尚不完全清楚。在这里，我们表明 SalB 可显著促进人骨髓来源内皮祖细胞（BM-EPC）的体外迁移和管状形成能力，并显著减轻过氧化氢（H2O2）诱导的细胞损伤。SalB 可下调 Nox4 和 eNOS 以及烟酰胺腺嘌呤二核苷酸磷酸（NADPH）-氧化酶的表达，从而防止氧化诱导的内皮功能障碍。此外，SalB 可抑制 H2O2 诱导后的 Bax/Bcl-xL 比值和半胱天冬酶-3 活化。此外，我们的结果提供了机制证据，表明 mTOR/p70S6K/4EBP1 途径的激活对于 SalB 介导的血管生成以及对 BM-EPC 中氧化应激诱导的细胞损伤的保护作用是必需的。SalB 对 MKK3/6-p38 MAPK-ATF2 和 ERK1/2 信号通路的抑制可通过降低细胞内 ROS 水平和凋亡来显著保护 BM-EPC 免受氧化应激引起的细胞损伤。总之，通过提供 SalB 对 BM-EPC 中氧化还原状态调节的机制见解，我们表明 SalB 具有作为新的促血管生成和细胞保护治疗剂的强大潜力，可应用于内皮损伤介导的血管疾病领域。
