姜黄中分离得到的姜黄新素 A 通过 PI3K/Akt/eNOS 信号通路发挥血管舒张作用。

Vasorelaxant effect of curcubisabolanin A isolated from Curcuma longa through the PI3K/Akt/eNOS signaling pathway.

机构信息

State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Institute of Innovative Medicine Ingredients of Southwest Specialty Medicinal Materials, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.

出版信息

J Ethnopharmacol. 2022 Aug 10;294:115332. doi: 10.1016/j.jep.2022.115332. Epub 2022 May 5.

DOI:10.1016/j.jep.2022.115332

PMID:35525529

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Curcuma longa L. (Zingiberaceae) is a known blood-activating and stasis-removing traditional Chinese medicine and has relevant pharmacological properties. The rhizomes of C. longa have been used for the treatment of cardiovascular disease (CVD) in China. Previous studies have shown that sesquiterpenoids from C. longa have significant vasorelaxant effects, which are closely associated with the prevention and treatment of CVD.

AIM OF THE STUDY

To explore the sesquiterpenoids with vasorelaxant effects from C. longa and investigate the underlying mechanisms.

MATERIALS AND METHODS

The compound was isolated from C. longa by multiple chromatography technologies. Its structure was determined by extensive spectroscopic analyses, nuclear magnetic resonance (NMR) data calculations, electronic circular dichroism (ECD) data calculations, and optical rotation (OR) data calculations. The vasorelaxant effect of the isolated compound was evaluated by KCl- or phenylephrine (PHE)-inducing contraction of the rat thoracic aortic rings. Endothelial removal and L-NAME pretreatment experiments were used to verify the endothelium-dependent vasorelaxant effect of the isolated compound in rat thoracic aortic rings. NO production was monitored in human umbilical vein endothelial cells (HUVECs). Western blot was carried out in HUVECs to elucidate the potential mechanisms.

RESULTS

A new bisabolane-type sesquiterpenoid, curcubisabolanin A [(+)-(1S,7S,9E)-bisabola-2(3),4(15),9(10)-trien-11-ol], was isolated from the rhizomes of C. longa. curcubisabolanin A exhibited endothelium-dependent relaxation on rat thoracic aortic rings, while pre-treatment of intact aortic rings with an eNOS inhibitor (L-NAME) attenuated the vasorelaxant response of curcubisabolanin A. In addition, curcubisabolanin A induced intracellular NO production and significantly increased the levels of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), and phosphorylated eNOS (p-eNOS) in HUVECs. LY294002 (a blocker of PI3K) and MK-2206 (a highly selective inhibitor of Akt) significantly decreased these effects of curcubisabolanin A.

CONCLUSIONS

These findings demonstrated that the vasorelaxant effect of curcubisabolanin A was partially endothelium-dependent and was related to regulation of NO production in vascular endothelial cells through the PI3K/Akt/eNOS signaling pathway.

摘要

民族药理学相关性

姜黄（姜科）是一种已知的活血祛瘀的中药，具有相关的药理学特性。姜黄的根茎在中国被用于治疗心血管疾病（CVD）。先前的研究表明，姜黄中的倍半萜类化合物具有显著的血管舒张作用，这与 CVD 的预防和治疗密切相关。

研究目的

探索姜黄中具有血管舒张作用的倍半萜类化合物，并研究其潜在机制。

材料与方法

采用多种色谱技术从姜黄中分离得到化合物。通过广泛的光谱分析、核磁共振（NMR）数据计算、电子圆二色性（ECD）数据计算和旋光度（OR）数据计算确定其结构。采用 KCl 或苯肾上腺素（PHE）诱导大鼠胸主动脉环收缩来评价分离得到的化合物的血管舒张作用。通过内皮细胞去除和 L-NAME 预处理实验验证分离得到的化合物在大鼠胸主动脉环中的内皮依赖性血管舒张作用。在人脐静脉内皮细胞（HUVECs）中监测 NO 产生。在 HUVECs 中进行 Western blot 以阐明潜在机制。

结果

从姜黄的根茎中分离得到一种新的倍半萜类化合物，姜黄环二烯 A[(+)-(1S,7S,9E)-bisabola-2(3),4(15),9(10)-trien-11-ol]。姜黄环二烯 A 对大鼠胸主动脉环表现出内皮依赖性舒张作用，而用 eNOS 抑制剂（L-NAME）预处理完整的主动脉环则减弱了姜黄环二烯 A 的血管舒张反应。此外，姜黄环二烯 A 诱导细胞内 NO 产生，并显著增加 HUVECs 中磷酸化 PI3K（p-PI3K）、磷酸化 Akt（p-Akt）和磷酸化 eNOS（p-eNOS）的水平。LY294002（PI3K 阻断剂）和 MK-2206（Akt 的高选择性抑制剂）显著降低了姜黄环二烯 A 的这些作用。