伊诺斯
KLF2
下调和上调
细胞生物学
一氧化氮
内皮功能障碍
安普克
化学
生物
内分泌学
磷酸化
生物化学
内科学
一氧化氮合酶
蛋白激酶A
医学
基因
作者
Gi Ho Lee,Jin Song Park,Sun Woo Jin,Thi Hoa Pham,Tuyet Ngan Thai,Ji Yeon Kim,Chae Yeon Kim,Jae Ho Choi,Eun Hee Han,Hye Gwang Jeong
标识
DOI:10.1021/acs.jafc.0c06250
摘要
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.
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