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On-line Access: 2022-12-15

Received: 2022-06-27

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 ORCID:

Wenhui DING

https://orcid.org/0000-0003-1322-8269

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Globular adiponectin-mediated vascular remodeling by affecting the secretion of adventitial-derived tumor necrosis factor-α induced by urotensin II


Author(s):  Jun LI, Limin LUO, Yonggang ZHANG, Xiao DONG, Shuyi DANG, Xiaogang GUO, Wenhui DING

Affiliation(s):  Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; more

Corresponding email(s):  dwh_rd@126.com

Key Words:  Urotensin II; Adiponectin; Signal transduction; Adventitial fibroblast; RNA interference (RNAi); Adiponectin-knockout (APN-KO)


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Jun LI, Limin LUO, Yonggang ZHANG, Xiao DONG, Shuyi DANG, Xiaogang GUO, Wenhui DING. Globular adiponectin-mediated vascular remodeling by affecting the secretion of adventitial-derived tumor necrosis factor-α induced by urotensin II[J]. Journal of Zhejiang University Science B, 2022, 23(4): 1014-1027.

@article{title="Globular adiponectin-mediated vascular remodeling by affecting the secretion of adventitial-derived tumor necrosis factor-α induced by urotensin II",
author="Jun LI, Limin LUO, Yonggang ZHANG, Xiao DONG, Shuyi DANG, Xiaogang GUO, Wenhui DING",
journal="Journal of Zhejiang University Science B",
volume="23",
number="12",
pages="1014-1027",
year="2022",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200346"
}

%0 Journal Article
%T Globular adiponectin-mediated vascular remodeling by affecting the secretion of adventitial-derived tumor necrosis factor-α induced by urotensin II
%A Jun LI
%A Limin LUO
%A Yonggang ZHANG
%A Xiao DONG
%A Shuyi DANG
%A Xiaogang GUO
%A Wenhui DING
%J Journal of Zhejiang University SCIENCE B
%V 23
%N 12
%P 1014-1027
%@ 1673-1581
%D 2022
%I Zhejiang University Press & Springer

TY - JOUR
T1 - Globular adiponectin-mediated vascular remodeling by affecting the secretion of adventitial-derived tumor necrosis factor-α induced by urotensin II
A1 - Jun LI
A1 - Limin LUO
A1 - Yonggang ZHANG
A1 - Xiao DONG
A1 - Shuyi DANG
A1 - Xiaogang GUO
A1 - Wenhui DING
J0 - Journal of Zhejiang University Science B
VL - 23
IS - 12
SP - 1014
EP - 1027
%@ 1673-1581
Y1 - 2022
PB - Zhejiang University Press & Springer
ER -


Abstract: 
ObjectivesIn this study, we explored how adiponectin mediated urotensin II (UII)‍-induced tumor necrosis factor-‍α(TNF-‍α) andα‍-smooth muscle actin (α‍-SMA) expression and ensuing intracellular signaling pathways in adventitial fibroblasts (AFs).
MethodsGrowth-arrested AFs and rat tunica adventitia of vessels were incubated with UII and inhibitors of signal transduction pathways for 1‍‒‍24 h. The cells were then harvested for TNF-αreceptor (TNF-‍α-R) messenger RNA (mRNA) and TNF-‍αprotein expression determination by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Adiponectin and adiponectin receptor (adipoR) expression was measured by RT-PCR, quantitative real-time PCR (qPCR), immunohistochemical analysis, and cell counting kit-8 (CCK-8) cell proliferation experiments. We then quantified TNF-α and α-SMA mRNA and protein expression levels by qPCR and immunofluorescence (IF) staining. RNA interference (RNAi) was used to explore the function of the adipoR genes. To investigate the signaling pathway, we applied western blotting (WB) to examine phosphorylation of adenosine 5'-monophosphate (AMP)‍-activated protein kinase (AMPK). In vivo, an adiponectin (APN)‍-knockout (APN-KO) mouse model mimicking adventitial inflammation was generated to measure TNF-α and α‍-SMA expression by application of qPCR and IF, with the goal of gaining a comprehensive atlas of adiponectin in vascular remodeling.
ResultsIn both cells and tissues, UII promoted TNF-α protein and TNF-α-R secretion in a dose- and time-dependent manner via Rho/protein kinase C (PKC) pathway. We detected marked expression of adipoR1, T-cadherin, and calreticulin as well as a moderate presence of adipoR2 in AFs, while no adiponectin was observed. Globular adiponectin (gAd) fostered the growth of AFs, and acted in concert with UII to induce α-SMA and TNF-α through the adipoR1/T-cadherin/calreticulin/AMPK pathway. In AFs, gAd and UII synergistically induced AMPK phosphorylation. In the adventitial inflammation model, APN deficiency up-regulated the expression of α-SMA, UII receptor (UT), and UII while inhibiting TNF-‍αexpression.
ConclusionsFrom the results of our study, we can speculate that UII induces TNF‍-‍αprotein and TNF-‍α‍-R secretion in AFs and rat tunica adventitia of vessels via the Rho and PKC signal transduction pathways. Thus, it is plausible that adiponectin is a major player in adventitial progression and could serve as a novel therapeutic target for cardiovascular disease administration.

球型脂联素对尾加压素II诱导血管外膜分泌肿瘤坏死因子介导血管重构的影响

李军1,2,3,罗丽敏4,张勇刚5,董晓2,党书毅2,郭晓纲1,丁文惠3
1浙江大学医学院附属第一医院心内科,浙江杭州,310003
2湖北医药学院附属太和医院心内科,湖北十堰,442000
3北京大学第一医院心内科,北京,100034
4浙江大学医学院附属第一医院皮肤科,浙江杭州,310003
5汕头大学医学院附属第二医院心内科,广东汕头,515041
背景:血管外膜炎症在血管重构的发生发展过程中起着非常重要的作用。已有众多研究提示尾加压素II(UII)和脂联素(APN)在调节细胞免疫、代谢、炎症和凋亡方面具有作用。然而,关于它们对血管外膜重构的重要指示因子α-平滑肌肌动蛋白(α-SMA)和肿瘤坏死因子α(TNF-α)表达的影响所知有限。
目的:探索APN如何介导UII诱导的血管外膜分泌TNF-α和α-SMA及其信号转导通路机制。
方法:在体外实验中,将原代培养的大鼠血管外膜成纤维细胞(AFs)和血管外膜组织,用UII、APN和各种信号通路阻断剂孵育1~24小时。收集细胞和组织,分别采用RT-PCR和ELISA检测TNF-α及其受体mRNA和蛋白表达。采用RT-PCR、qPCR、免疫组化、CCK-8等检测APN及其受体(adipoR)的表达。然后通过qPCR和免疫荧光染色(IF)检测TNF-α和α-SMA蛋白和mRNA表达水平。采用RNA干扰(RNAi)研究adipoR基因的功能。应用western blotting观察AMPK磷酸化情况来研究信号通路。在体内实验中,建立APN基因敲除小鼠颈动脉外膜炎症模型,应用qPCR和IF检测TNF-α和α-SMA的表达。
结果:在细胞和组织中,UII通过Rho/PKC途径以剂量和时间依赖性的方式促进TNF-α及其受体的表达。adipoR1、T-cadherin和calreticulin在AFs中高表达,adipoR2低表达,没有观察到APN在AFs中表达。gAd与UII通过adipoR1/T-cadherin/calreticulin/AMPK途径协同而非抑制AFs中α-SMA和TNF-α的表达。同时,gAd和UII能够协同诱导AMPK磷酸化。在APN基因敲除小鼠构建的颈动脉外膜炎症模型中,APN的缺失可上调α-SMA、UII受体(UT)和UII的表达,而抑制TNF-α的表达。
结论:根据我们的研究结果,可以推测UII通过Rho和PKC信号转导通路诱导AFs和大鼠血管外膜中TNF-α及其受体的分泌。APN在血管外膜炎症性疾病的发生发展过程中扮演了重要角色,并可能成为心血管疾病治疗的新靶点。

关键词组:尾加压素II;脂联素;信号转导;血管外膜成纤维细胞;RNA干扰;脂联素基因敲除

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AmesRS, SarauHM, ChambersJK, et al., 1999. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature, 401(6750):282-286.

[2]AvagimyanA, KajaiaA, GabuniaL, et al., 2022. Urotensin-II as a promising key-point of cardiovascular disturbances sequel. Curr Probl Cardiol, 47(11):101074.

[3]BobbertP, AntoniakS, SchultheissHP, et al., 2008. Globular adiponectin but not full-length adiponectin induces increased procoagulability in human endothelial cells. J Mol Cell Cardiol, 44(2):388-394.

[4]DongX, YeXJ, SongNN, et al., 2013. Urotensin II promotes the production of LTC4 in rat aortic adventitial fibroblasts through NF-κB-5-LO pathway by p38 MAPK and ERK activations. Heart Vessels, 28(4):514-523.

[5]EnzerinkA, VaheriA, 2011. Fibroblast activation in vascular inflammation. J Thromb Haemost, 9(4):619-626.

[6]EvansBR, YerlyA, van der VorstEPC, et al., 2022. Inflammatory mediators in atherosclerotic vascular remodeling. Front Cardiovasc Med, 9:868934.

[7]HassanGS, DouglasSA, OhlsteinEH, et al., 2005. Expression of urotensin-II in human coronary atherosclerosis. Peptides, 26(12):2464-2472.

[8]LauWB, OhashiK, WangYJ, et al., 2017. Role of adipokines in cardiovascular disease. Circ J, 81(7):920-928.

[9]LiAC, GlassCK, 2002. The macrophage foam cell as a target for therapeutic intervention. Nat Med, 8(11):1235-1242.

[10]LiuLH, ShiZH, JiXH, et al., 2022. Adipokines, adiposity, and atherosclerosis. Cell Mol Life Sci, 79(5):272.

[11]LuD, PengF, LiJ, et al., 2019. Urotensin II promotes secretion of LTB4 through 5-lipoxygenase via the UT-ROS-Akt pathway in RAW264.7 macrophages. Arch Med Sci, 15(4):1065-1072.

[12]NosalskiR, GuzikTJ, 2017. Perivascular adipose tissue inflammation in vascular disease. Br J Pharmacol, 174(20):3496-3513.

[13]ParkSL, LeeBK, KimYA, et al., 2013. Inhibitory effect of an urotensin II receptor antagonist on proinflammatory activation induced by urotensin II in human vascular endothelial cells. Biomol Ther (Seoul), 21(4):277-283.

[14]Pereira-CastroJ, Brás-SilvaC, Fontes-SousaAP, 2019. Novel insights into the role of urotensin II in cardiovascular disease. Drug Discov Today, 24(11):2170-2180.

[15]RamiAZA, HamidAA, AnuarNNM, et al., 2022. Exploring the relationship of perivascular adipose tissue inflammation and the development of vascular pathologies. Mediators Inflamm, 2022:2734321.

[16]RuanH, DongLQ, 2016. Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol, 8(2):101-109.

[17]SowkaA, DobrzynP, 2021. Role of perivascular adipose tissue-derived adiponectin in vascular homeostasis. Cells, 10(6):1485.

[18]StenmarkKR, YeagerME, el KasmiKC, et al., 2013. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol, 75:23-47.

[19]TinajeroMG, GotliebAI, 2020. Recent developments in vascular adventitial pathobiology: the dynamic adventitia as a complex regulator of vascular disease. Am J Pathol, 190(3):520-534.

[20]von der ThüsenJH, van BerkelTJC, BiessenEAL, 2001. Induction of rapid atherogenesis by perivascular carotid collar placement in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Circulation, 103(8):1164-1170.

[21]WangZV, SchererPE, 2016. Adiponectin, the past two decades. J Mol Cell Biol, 8(2):93-100.

[22]WatsonAMD, OlukmanM, KoulisC, et al., 2013. Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes. Diabetologia, 56(5):1155-1165.

[23]YamauchiT, KamonJ, ItoY, et al., 2003. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature, 423(6941):762-769.

[24]ZhangR, WuJ, LiuD, et al., 2013. Anti-inflammatory effect of full-length adiponectin and proinflammatory effect of globular adiponectin in esophageal adenocarcinoma cells. Oncol Res, 21(1):15-21.

[25]ZhangYG, LiYG, WeiRH, et al., 2008a. Urotensin II is an autocrine/paracrine growth factor for aortic adventitia of rat. Regul Pept, 151(1-3):88-94.

[26]ZhangYG, LiJ, LiYG, et al., 2008b. Urotensin II induces phenotypic differentiation, migration, and collagen synthesis of adventitial fibroblasts from rat aorta. J Hypertens, 26(6):1119-1126.

[27]ZhangYG, HuYC, MaoYY, et al., 2010. Transforming growth factor-β1 involved in urotensin II-induced phenotypic differentiation of adventitial fibroblasts from rat aorta. Chin Med J (Engl), 123(24):3634-3639.

[28]ZhangYG, BaoSL, KuangZJ, et al., 2014. Urotensin II promotes monocyte chemoattractant protein-1 expression in aortic adventitial fibroblasts of rat. Chin Med J (Engl), 127(10):1907-1912.

[29]ZhaoK, YangCX, LiP, et al., 2020. Epigenetic role of N6-methyladenosine (m6A) RNA methylation in the cardiovascular system. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(7):509-523.

[30]ZhaoK, ZhangJ, XuTH, et al., 2021. Low-intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(10):818-838.

[31]ZhouX, LiJQ, WeiLJ, et al., 2020. Silencing of DsbA-L gene impairs the PPARγ agonist function of improving insulin resistance in a high-glucose cell model. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(12):‍990-998.

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