摘要:
A variety of cardiovascular diseases is accompanied by the loss of vascular contractility. This study sought to investigate the effects of curcumin, a natural polyphenolic compound present in turmeric, on mouse vascular contractility and the underlying mechanisms. After mice were administered curcumin (100 mg.kg(-1).d(-1), ig) for 6 weeks, the contractile responses of the thoracic aorta to KCl and phenylephrine were significantly enhanced compared with the control group. Furthermore, the contractility of vascular smooth muscle (SM) was significantly enhanced after incubation in curcumin (25 mu mol/L) for 4 d, which was accompanied by upregulated expression of SM marker contractile proteins SM22 alpha and SM alpha-actin. In cultured vascular smooth muscle cells (VSMCs), curcumin (10, 25, 50 mu mol/L) significantly increased the expression of myocardin, a "master regulator" of SM gene expression. Curcumin treatment also significantly increased the levels of caveolin-1 in VSMCs. We found that as a result of the upregulation of caveolin-1, curcumin blocked the activation of Notch1 and thereby abolished Notch1-inhibited myocardin expression. Knockdown of caveolin-1 or activation of Notch1 signaling with Jagged1 (2 mu g/mL) diminished these effects of curcumin in VSMCs. These findings suggest that curcumin induces the expression of myocardin in mouse smooth muscle cells via a variety of mechanisms, including caveolin-1-mediated inhibition of Notch1 activation and Notch1-mediated repression of myocardin expression. This may represent a novel pathway, through which curcumin protects blood vessels via the beneficial regulation of SM contractility.
期刊:
Biochemical and Biophysical Research Communications,2016年480(1):139-145 ISSN:0006-291X
通讯作者:
Chen, Jianxiong;Tuo, QH
作者机构:
[Xu, Guina; Sun, Shaowei; Wen, Juan; Xiong, Guozuo; Li, Tianping; Zhang, Caiping] Univ South China, Inst Pharm & Pharmacol, Sch Life Sci & Technol, Hengyang 421001, Hunan, Peoples R China.;[Nie, Juan; Tuo, Qinhui; Chen, Jianxiong; Chen, JX; Sun, Shaowei; Qiu, Fei; Liao, Duangfang] Hunan Univ Chinese Med, Sch Med, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.;[Yin, Yufang] Southern Illinois Univ, Dept Pharmacol, Sch Med, Springfield, IL 62702 USA.;[Chen, Jianxiong] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Jackson, MS 39216 USA.
通讯机构:
[Chen, JX; Tuo, QH ] H;Hunan Univ Chinese Med, Sch Med, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.
关键词:
*Androgen receptor;*Cholesterol;*Fas death domain-associated protein;*SCAP;*SREBP
摘要:
Daxx is a highly conserved nuclear transcriptional factor, which has been implicated in many nuclear processes including transcription and cell cycle regulation. Our previous study demonstrated Daxx also plays a role in regulation of intracellular cholesterol content. Daxx contains several domains that are essential for interaction with a growing number of proteins. To delineate the underlying mechanism of hypocholesterolemic activity of Daxx, we constructed a set of plasmids which can be used to overexpress different fragments of Daxx and transfected to HepG2 cells. We found that the C-terminal region Daxx626-740 clearly reduced intracellular cholesterol levels and inhibited the expression of SREBPs and SCAR. In GST pull-down experiments and Double immunofluorescence assays, Daxx626-740 was demonstrated to bind directly to androgen receptor (AR). Our findings suggest that the interaction of Daxx626-740 and AR abolishes the AR-mediated activation of SCAP/SREBPs pathway, which suppresses the de novo cholesterol synthesis. Thus, C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol content in HepG2 cells. (C) 2016 Elsevier Inc. All rights reserved.