Targeting the Ang2/Tie2 Axis with Tanshinone IIA Elicits Vascular Normalization in Ischemic Injury and Colon Cancer.
Targeting the Ang2/Tie2 Axis with Tanshinone IIA Elicits Vascular Normalization in Ischemic Injury and Colon Cancer.
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DOI：
10.1155/2021/7037786
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发表时间：
2021
影响因子：
--
通讯作者：
Lu Y
中科院分区：
文献类型：
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作者：
Zou W;Qian C;Zhang S;Wan X;Wei Z;Li X;Wu Y;Chen W;Wang A;Zhao Y;Lu Y
病理性血管生成，如异常的血管结构和功能所表现的，已经被认为是癌症和各种缺血性疾病的标志。因此，使脉管系统正常化的策略在这些疾病中具有潜在的治疗兴趣。最近，从药用植物提取物中鉴定生物活性化合物以逆转异常血管系统已经获得越来越多的关注。丹参酮IIA（Tanshinone IIA，Tan IIA）是丹参的有效成分，具有改善血液循环、延缓肿瘤进展等作用。然而，Tan IIA治疗效果的潜在机制尚未完全了解。在此，我们建立了HT-29人结肠癌异种移植和后肢缺血的动物模型，以研究Tan IIA在调节异常血管中的作用。有趣的是，我们的研究结果表明，谭IIA可以显着促进血流，缓解缺氧，改善肌肉质量，并改善缺血损伤后的病理损伤。同时，我们还发现Tan IIA促进HT-29肿瘤血管结构的完整性，减少血管渗漏，并减轻缺氧。此外，在这两种病理状态下极高的循环血管生成素2（Ang 2）在Tan IIA存在下基本上耗尽。此外，Tie 2的激活被Tan IIA增强，导致血管通透性降低和血管完整性升高。在机制上，我们发现Tan IIA通过靶向Ang 2-Tie 2-AKT-MLCK级联维持血管稳定性。总的来说，我们的数据表明，Tan IIA通过调节Ang 2/Tie 2信号通路使肿瘤和缺血性损伤中的血管正常化。
Pathological angiogenesis, as exhibited by aberrant vascular structure and function, has been well deemed to be a hallmark of cancer and various ischemic diseases. Therefore, strategies to normalize vasculature are of potential therapeutic interest in these diseases. Recently, identifying bioactive compounds from medicinal plant extracts to reverse abnormal vasculature has been gaining increasing attention. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza, has been shown to play significant roles in improving blood circulation and delaying tumor progression. However, the underlying mechanisms responsible for the therapeutic effects of Tan IIA are not fully understood. Herein, we established animal models of HT-29 human colon cancer xenograft and hind limb ischemia to investigate the role of Tan IIA in regulating abnormal vasculature. Interestingly, our results demonstrated that Tan IIA could significantly promote the blood flow, alleviate the hypoxia, improve the muscle quality, and ameliorate the pathological damage after ischemic insult. Meanwhile, we also revealed that Tan IIA promoted the integrity of vascular structure, reduced vascular leakage, and attenuated the hypoxia in HT-29 tumors. Moreover, the circulating angiopoietin 2 (Ang2), which is extremely high in these two pathological states, was substantially depleted in the presence of Tan IIA. Also, the activation of Tie2 was potentiated by Tan IIA, resulting in decreased vascular permeability and elevated vascular integrity. Mechanistically, we uncovered that Tan IIA maintained vascular stability by targeting the Ang2-Tie2-AKT-MLCK cascade. Collectively, our data suggest that Tan IIA normalizes vessels in tumors and ischemic injury via regulating the Ang2/Tie2 signaling pathway.