桦木酸通过依赖AMPK的KLF2信号通路诱导eNOS表达,Journal of Agricultural and Food Chemistry - X-MOL

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桦木酸通过依赖AMPK的KLF2信号通路诱导eNOS表达
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2020-11-24 , DOI: 10.1021/acs.jafc.0c06250
Gi Ho Lee ₁ , Jin Song Park ₁ , Sun Woo Jin ₁ , Thi Hoa Pham ₁ , Tuyet Ngan Thai ₁ , Ji Yeon Kim ₁ , Chae Yeon Kim ₁ , Jae Ho Choi ₁ , Eun Hee Han ₂ , Hye Gwang Jeong ₁

Affiliation

桦木酸（BA）是一种天然的五环三萜类化合物，对炎症，代谢性疾病和心血管疾病具有保护作用。我们以前已经证明，BA通过激活人内皮细胞中的内皮一氧化氮合酶（eNOS）来增加一氧化氮（NO）的合成，从而预防内皮功能障碍。但是，BA对eNOS表达的影响仍不清楚。因此，我们研究的目的是研究与BA调节人内皮细胞中eNOS表达相关的细胞内途径。BA以时间和浓度依赖性方式显着增加eNOS表达。此外，BA上调了转录因子KLF2的表达，已知该因子可调控eNOS的表达。人内皮细胞中的KLF2沉默减弱了BA上调eNOS的能力。BA还增加了细胞内钙的水平²⁺激活CaMKKβ，CaMKIIα和AMPK。TRPC钙通道的抑制作用消除了BA介导的对细胞内Ca ²⁺水平的影响。此外，BA增加了ERK5，HDAC5和MEF2C的磷酸化水平。用化合物C（AMPK抑制剂），LMK235（HDAC5抑制剂）和XMD8-92（ERK5抑制剂）预处理细胞会减弱BA诱导的eNOS表达。总的来说，这些发现表明BA通过激活内皮细胞中的HDAC5 / ERK5 / KLF2途径来诱导eNOS表达。此处提供的数据提供了有力的证据，支持使用BA预防内皮功能障碍和治疗血管疾病，例如动脉粥样硬化。

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Betulinic Acid Induces eNOS Expression via the AMPK-Dependent KLF2 Signaling Pathway

Betulinic acid (BA) is a natural pentacyclic triterpenoid with protective effects against inflammation, metabolic diseases, and cardiovascular diseases. We have previously shown that BA prevents endothelial dysfunction by increasing nitric oxide (NO) synthesis through activating endothelial nitric oxide synthase (eNOS) in human endothelial cells. However, the effect of BA on eNOS expression remains unclear. Thus, the aim of our study was to investigate the intracellular pathways associated with the effect of BA to regulate eNOS expression in human endothelial cells. BA significantly increased eNOS expression in a time- and concentration-dependent manner. Additionally, BA upregulated the expression of the transcription factor KLF2, which is known to regulate eNOS expression. KLF2 silencing in human endothelial cells attenuated the ability of BA to upregulate eNOS. BA also increased levels of intracellular Ca²⁺, activating CaMKKβ, CaMKIIα, and AMPK. Inhibition of the TRPC calcium channel abolished BA-mediated effects on intracellular Ca²⁺ levels. Moreover, BA increased the phosphorylation levels of ERK5, HDAC5, and MEF2C. Pretreatment of cells with compound C (AMPK inhibitor), LMK235 (HDAC5 inhibitor), and XMD8-92 (ERK5 inhibitor) attenuated the BA-induced eNOS expression. Collectively, these findings suggest that BA induces eNOS expression by activating the HDAC5/ERK5/KLF2 pathway in endothelial cells. The data presented here provide strong evidence supporting the use of BA to prevent endothelial dysfunction and treat vascular diseases, such as atherosclerosis.

更新日期：2020-12-09

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