Zhang Jianqi, Nugrahaningrum Dyah Ari, Marcelina Olivia, Ariyanti Agnes Dwi, Wang Guixue, Liu Caiping, Wu Shourong, Kasim Vivi
The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China.
Front Pharmacol. 2019 Aug 14;10:909. doi: 10.3389/fphar.2019.00909. eCollection 2019.
As one of the most severe manifestations of diabetes, vascular complications are the main causes of diabetes-related morbidity and mortality. Hyperglycemia induces systemic abnormalities, including impaired angiogenesis, causing diabetic patients to be highly susceptible in suffering hindlimb ischemia (HLI). Despite its severe prognosis, there is currently no effective treatment for diabetic HLI. Skeletal muscle cells secrete multiple angiogenic factors, hence, recently are reported to be critical for angiogenesis; however, hyperglycemia disrupted the paracrine function in skeletal muscle cells, leading to the impaired angiogenesis potential observed in diabetic patients. The present study showed that tyrosol, a phenylethanoid compound, suppresses accumulation of intracellular reactive oxygen species (ROS) caused by hyperglycemia, most plausibly by promoting heme oxygenase-1 (HO-1) expression in skeletal muscle cells. Consequently, tyrosol exerts cytoprotective function against hyperglycemia-induced oxidative stress in skeletal muscle cells, increases their proliferation vigorously, and simultaneously suppresses apoptosis. Furthermore, tyrosol grossly increases the secretion of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) from skeletal muscle cells. This leads to enhanced proliferation and migration capabilities of vascular endothelial and smooth muscle cells, two types of cells that are responsible in forming blood vessels, through cell-cell communication. Finally, experiment using the diabetic HLI mouse model showed that tyrosol injection into the gastrocnemius muscle of the ischemic hindlimb significantly enhances the formation of functional blood vessels and subsequently leads to significant recovery of blood perfusion. Overall, our findings highlight the potential of the pharmacological application of tyrosol as a small molecule drug for therapeutic angiogenesis in diabetic HLI patients.
作为糖尿病最严重的表现之一，血管并发症是糖尿病相关发病和死亡的主要原因。高血糖会引发全身异常，包括血管生成受损，导致糖尿病患者极易发生后肢缺血（HLI）。尽管预后严重，但目前尚无针对糖尿病性HLI的有效治疗方法。骨骼肌细胞分泌多种血管生成因子，因此，最近有报道称其对血管生成至关重要；然而，高血糖破坏了骨骼肌细胞的旁分泌功能，导致糖尿病患者观察到血管生成潜力受损。本研究表明，酪醇是一种苯乙醇类化合物，它最有可能通过促进骨骼肌细胞中血红素加氧酶-1（HO-1）的表达来抑制高血糖引起的细胞内活性氧（ROS）积累。因此，酪醇对骨骼肌细胞中高血糖诱导的氧化应激发挥细胞保护作用，大力增加其增殖，并同时抑制细胞凋亡。此外，酪醇显著增加骨骼肌细胞中血管内皮生长因子-A（VEGF-A）和血小板衍生生长因子-BB（PDGF-BB）的分泌。通过细胞间通讯，这导致负责形成血管的两种细胞类型，即血管内皮细胞和平滑肌细胞的增殖和迁移能力增强。最后，使用糖尿病性HLI小鼠模型进行的实验表明，向缺血后肢的腓肠肌注射酪醇可显著增强功能性血管的形成，并随后导致血液灌注的显著恢复。总体而言，我们的研究结果突出了酪醇作为一种小分子药物在糖尿病性HLI患者治疗性血管生成中的药理学应用潜力。
