Full Text:   <351>

Summary:  <70>

Suppl. Mater.: 

CLC number: 

On-line Access: 2022-12-15

Received: 2022-06-27

Revision Accepted: 2022-08-17

Crosschecked: 2022-12-15

Cited: 0

Clicked: 292

Citations:  Bibtex RefMan EndNote GB/T7714


Wenhui DING


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2022 Vol.23 No.12 P.1014-1027


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)

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(12): 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",
publisher="Zhejiang University Press & Springer",

%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
%DOI 10.1631/jzus.B2200346

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 -
DOI - 10.1631/jzus.B2200346

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.


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。


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


[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.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2023 Journal of Zhejiang University-SCIENCE