Full Text:   <2102>

Summary:  <1078>

Suppl. Mater.: 

CLC number: 

On-line Access: 2021-10-12

Received: 2021-02-04

Revision Accepted: 2021-07-01

Crosschecked: 0000-00-00

Cited: 0

Clicked: 3168

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Bin ZHOU

https://orcid.org/0000-0002-5486-2285

Wei SUN

https://orcid.org/0000-0003-0833-0445

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2021 Vol.22 No.10 P.818-838

http://doi.org/10.1631/jzus.B2100130


Low‐intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway


Author(s):  Kun ZHAO, Jing ZHANG, Tianhua XU, Chuanxi YANG, Liqing WENG, Tingting WU, Xiaoguang WU, Jiaming MIAO, Xiasheng GUO, Juan TU, Dong ZHANG, Bin ZHOU, Wei SUN, Xiangqing KONG

Affiliation(s):  Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; more

Corresponding email(s):   weisun7919@njmu.edu.cn, bin.zhou@einstein.yu.edu

Key Words:  Low-intensity pulsed ultrasound (LIPUS), Caveolin-1, Cardiac fibrosis, Inflammation, Angiotensin II (AngII)


Kun ZHAO, Jing ZHANG, Tianhua XU, Chuanxi YANG, Liqing WENG, Tingting WU, Xiaoguang WU, Jiaming MIAO, Xiasheng GUO, Juan TU, Dong ZHANG, Bin ZHOU, Wei SUN, Xiangqing KONG. Low‐intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway[J]. Journal of Zhejiang University Science B, 2021, 22(10): 818-838.

@article{title="Low‐intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway",
author="Kun ZHAO, Jing ZHANG, Tianhua XU, Chuanxi YANG, Liqing WENG, Tingting WU, Xiaoguang WU, Jiaming MIAO, Xiasheng GUO, Juan TU, Dong ZHANG, Bin ZHOU, Wei SUN, Xiangqing KONG",
journal="Journal of Zhejiang University Science B",
volume="22",
number="10",
pages="818-838",
year="2021",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2100130"
}

%0 Journal Article
%T Low‐intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway
%A Kun ZHAO
%A Jing ZHANG
%A Tianhua XU
%A Chuanxi YANG
%A Liqing WENG
%A Tingting WU
%A Xiaoguang WU
%A Jiaming MIAO
%A Xiasheng GUO
%A Juan TU
%A Dong ZHANG
%A Bin ZHOU
%A Wei SUN
%A Xiangqing KONG
%J Journal of Zhejiang University SCIENCE B
%V 22
%N 10
%P 818-838
%@ 1673-1581
%D 2021
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2100130

TY - JOUR
T1 - Low‐intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway
A1 - Kun ZHAO
A1 - Jing ZHANG
A1 - Tianhua XU
A1 - Chuanxi YANG
A1 - Liqing WENG
A1 - Tingting WU
A1 - Xiaoguang WU
A1 - Jiaming MIAO
A1 - Xiasheng GUO
A1 - Juan TU
A1 - Dong ZHANG
A1 - Bin ZHOU
A1 - Wei SUN
A1 - Xiangqing KONG
J0 - Journal of Zhejiang University Science B
VL - 22
IS - 10
SP - 818
EP - 838
%@ 1673-1581
Y1 - 2021
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2100130


Abstract: 
ObjectiveCardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by angiotensin II (AngII). low-intensity pulsed ultrasound (LIPUS) has been reported to ameliorate cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechano-transduction and its downstream pathways. In this study, we aimed to investigate whether LIPUS could exert a protective effect by ameliorating AngII-induced cardiac hypertrophy and fibrosis and if so, to further elucidate the underlying molecular mechanisms.
MethodsWe used AngII to mimic animal and cell culture models of cardiac hypertrophy and fibrosis. LIPUS irradiation was applied in vivo for 20 min every 2 d from one week before mini-pump implantation to four weeks after mini-pump implantation, and in vitro for 20 min on each of two occasions 6 h apart. Cardiac hypertrophy and fibrosis levels were then evaluated by echocardiographic, histopathological, and molecular biological methods.
ResultsOur results showed that LIPUS could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-induced release of inflammatory cytokines, but the protective effects on cardiac hypertrophy were limited in vitro. Given that LIPUS increased the expression of caveolin-1 in response to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vivo and in vitro. LIPUS-induced downregulation of inflammation was reversed and the anti-fibrotic effects of LIPUS were absent.
ConclusionsThese results indicated that LIPUS could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeutic apparatus in clinical practice.

低强度脉冲超声(LIPUS)通过小窝蛋白-1(caveolin-1)依赖性途径减轻炎症,从而改善血管紧张素II(AngII)诱导的心脏纤维化

目的:心肌肥厚和纤维化是血管紧张素II(AngII)引起的左心室重构的主要病理表现。既往研究表明低强度脉冲超声(LIPUS)能通过机械传导及其下游途径改善心肌梗死(MI)患者的心功能不全和心肌纤维化。因此,本研究旨在探讨LIPUS是否能改善AngII诱导的心肌肥厚和纤维化,并进一步阐明其潜在分子机制。
创新点:本研究首次发现LIPUS能通过机械敏感蛋白--小窝蛋白1(caveolin-1)减轻AngII引起的炎症反应,从而在体内和体外改善AngII引起的心肌纤维化。本研究为LIPUS今后在临床上用于预防和改善患者心肌纤维化损伤提供了理论依据。
方法:我们用AngII在体内和体外分别模拟心肌纤维化的动物和细胞模型。在体内,从术前1周到术后4周,每2天用LIPUS照射心前区20分钟;在体外,每隔6小时照射细胞20分钟,一共2次。然后,用超声心动图、组织病理学和分子生物学方法评价心肌肥大和纤维化水平。
结论:实验结果表明,LIPUS可通过降低AngII诱导的炎症细胞因子的释放,从而改善体内左室重构和体外心肌纤维化。但其对体外心肌肥大的保护作用有限。在机械刺激下,LIPUS能上调caveolin-1的表达。而进一步研究发现,在体内体外利用吡唑吡嘧啶2(pp2)预先抑制caveolin-1的活性后,LIPUS下调炎症反应和改善心肌纤维化的作用被明显逆转。以上结果表明,LIPUS可以通过caveolin-1依赖的途径减轻炎症,从而改善AngII诱导的心肌纤维化,并为这一新型治疗仪器的临床应用提供了新的思路和理论依据。

关键词:低强度脉冲超声(LIPUS);小窝蛋白-1(caveolin-1);心脏纤维化;炎症;血管紧张素II(AngII)

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

Reference

[1]AmesMK, AtkinsCE, PittB, 2019. The renin-angiotensin-aldosterone system and its suppression. J Vet Intern Med, 33(2):363-382.

[2]BuwaN, MazumdarD, BalasubramanianN, 2020. Caveolin1 tyrosine-14 phosphorylation: role in cellular responsiveness to mechanical cues. J Membr Biol, 253(6):509-534.

[3]ChenLY, WangX, QuXL, et al., 2019. Activation of the STAT3/microRNA-21 pathway participates in angiotensin II-induced angiogenesis. J Cell Physiol, 234(11):19640-19654.

[4]ChinnakkannuP, ReeseC, GasparJA, et al., 2018. Suppression of angiotensin II-induced pathological changes in heart and kidney by the caveolin-1 scaffolding domain peptide. PLoS ONE, 13(12):e0207844.

[5]ChungJW, KimDH, OhMJ, et al., 2018. Cav-1 (caveolin-1) and arterial remodeling in adult moyamoya disease. Stroke, 49(11):2597-2604.

[6]DesjardinsF, LobyshevaI, PelatM, et al., 2008. Control of blood pressure variability in caveolin-1-deficient mice: role of nitric oxide identified in vivo through spectral analysis. Cardiovasc Res, 79(3):527-536.

[7]DingL, ZengQM, WuJP, et al., 2017. Caveolin-1 regulates oxidative stress-induced senescence in nucleus pulposus cells primarily via the p53/p21 signaling pathway in vitro. Mol Med Rep, 16(6):9521-9527.

[8]DuerrschmidC, TrialJ, WangYL, et al., 2015. Tumor necrosis factor: a mechanistic link between angiotensin-II-induced cardiac inflammation and fibrosis. Circ Heart Fail, 8(2):352-361.

[9]ForresterSJ, ElliottKJ, KawaiT, et al., 2017. Caveolin-1 deletion prevents hypertensive vascular remodeling induced by angiotensin II. Hypertension, 69(1):79-86.

[10]FrangogiannisNG, 2021. Cardiac fibrosis. Cardiovasc Res, 117(6):1450-1488.

[11]GebremichaelY, LahuG, VakilynejadM, et al., 2019. Benchmarking renin suppression and blood pressure reduction of direct renin inhibitor imarikiren through quantitative systems pharmacology modeling. J Pharmacokinet Pharmacodyn, 46(1):15-25.

[12]GonzálezGE, RhalebNE, D'AmbrosioMA, et al., 2016. Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol, 311(5):H1287-H1296.

[13]GrivasD, González-RajalÁ, RodríguezCG, et al., 2020. Loss of Caveolin-1 and caveolae leads to increased cardiac cell stiffness and functional decline of the adult zebrafish heart. Sci Rep, 10:12816.

[14]GvaramiaD, BlaauboerME, HanemaaijerR, et al., 2013. Role of caveolin-1 in fibrotic diseases. Matrix Biol, 32(6):307-315.

[15]HannaA, FrangogiannisNG, 2020. Inflammatory cytokines and chemokines as therapeutic targets in heart failure. Cardiovasc Drugs Ther, 34(6):849-863.

[16]HendriksT, van DijkR, AlsabaanNA, et al., 2020. Active tobacco smoking impairs cardiac systolic function. Sci Rep, 10:6608.

[17]ItoA, ShirotoT, GodoS, et al., 2019. Important roles of endothelial caveolin-1 in endothelium-dependent hyperpolarization and ischemic angiogenesis in mice. Am J Physiol Heart Circ Physiol, 316(4):H900-H910.

[18]JiJJ, LiuZF, HongXX, et al., 2020. Protective effects of rolipram on endotoxic cardiac dysfunction via inhibition of the inflammatory response in cardiac fibroblasts. BMC Cardiovasc Disord, 20:242.

[19]JiangXX, SavchenkoO, LiYF, et al., 2019. A review of low-intensity pulsed ultrasound for therapeutic applications. IEEE Trans Biomed Eng, 66(10):2704-2718.

[20]JokhadarŠZ, MajhencJ, SvetinaS, et al., 2013. Positioning of integrin β1, caveolin-1 and focal adhesion kinase on the adhered membrane of spreading cells. Cell Biol Int, 37(12):1276-1284.

[21]KalamK, OtahalP, MarwickTH, 2014. Prognostic implications of global LV dysfunction: a systematic review and meta-analysis of global longitudinal strain and ejection fraction. Heart, 100(21):1673-1680.

[22]LennmyrF, EricssonA, GerwinsP, et al., 2004. Src family kinase-inhibitor PP2 reduces focal ischemic brain injury. Acta Neurol Scand, 110(3):175-179.

[23]LiJ, ZhangQ, RenC, et al., 2018. Low-intensity pulsed ultrasound prevents the oxidative stress induced endothelial-mesenchymal transition in human aortic endothelial cells. Cell Physiol Biochem, 45(4):1350-1365.

[24]LinYM, BadrealamKF, KuoWW, et al., 2021. Nerolidol improves cardiac function in spontaneously hypertensive rats by inhibiting cardiac inflammation and remodelling associated TLR4/NF-κB signalling cascade. Food Chem Toxicol, 147:111837.

[25]LiuJJ, SongC, XiaoQM, et al., 2015. Fluorofenidone attenuates TGF-β1-induced lung fibroblast activation via restoring the expression of caveolin-1. Shock, 43(2):201-207.

[26]MaZG, YuanYP, WuHM, et al., 2018. Cardiac fibrosis: new insights into the pathogenesis. Int J Biol Sci, 14(12):1645-1657.

[27]MarudamuthuAS, BhandaryYP, FanL, et al., 2019. Caveolin-1-derived peptide limits development of pulmonary fibrosis. Sci Transl Med, 11(522):eaat2848.

[28]MonmaY, ShindoT, EguchiK, et al., 2021. Low-intensity pulsed ultrasound ameliorates cardiac diastolic dysfunction in mice: a possible novel therapy for heart failure with preserved left ventricular ejection fraction. Cardiovasc Res, 117(5):1325-1338.

[29]NakamuraM, SadoshimaJ, 2018. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol, 15(7):387-407.

[30]NetheM, HordijkPL, 2011. A model for phospho-caveolin-1-driven turnover of focal adhesions. Cell Adh Migr, 5(1): 59-64.

[31]NguyenTP, QuZL, WeissJN, 2014. Cardiac fibrosis and arrhythmogenesis: the road to repair is paved with perils. J Mol Cell Cardiol, 70:83-91.

[32]OgataT, ItoK, ShindoT, et al., 2017. Low-intensity pulsed ultrasound enhances angiogenesis and ameliorates contractile dysfunction of pressure-overloaded heart in mice. PLoS ONE, 12(9):e0185555.

[33]PartonRG, TilluVA, CollinsBM, 2018. Caveolae. Curr Biol, 28(8):R402-R405.

[34]PorterKE, TurnerNA, 2009. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther, 123(2):255-278.

[35]RazaniB, ZhangXL, BitzerM, et al., 2001. Caveolin-1 regulates transforming growth factor (TGF)‍-‍β/SMAD signaling through an interaction with the TGF-βtype I receptor. J Biol Chem, 276(9):6727-6738.

[36]RenLX, YangZ, SongJL, et al., 2013. Involvement of p38 MAPK pathway in low intensity pulsed ultrasound induced osteogenic differentiation of human periodontal ligament cells. Ultrasonics, 53(3):686-690.

[37]RibeiroS, PereiraARS, PintoAT, et al., 2019. Echocardiographic assessment of cardiac anatomy and function in adult rats. J Vis Exp, 154:e60404.

[38]RosenkranzS, 2004. TGF-β1 and angiotensin networking in cardiac remodeling. Cardiovasc Res, 63(3):423-432.

[39]SaucermanJJ, TanPM, BuchholzKS, et al., 2019. Mechanical regulation of gene expression in cardiac myocytes and fibroblasts. Nat Rev Cardiol, 16(6):361-378.

[40]SchlüterKD, WenzelS, 2008. Angiotensin II: a hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks. Pharmacol Ther, 119(3):311-325.

[41]SheG, RenYJ, WangY, et al., 2019. KCa3.1 channels promote cardiac fibrosis through mediating inflammation and differentiation of monocytes into myofibroblasts in angiotensin II-treated rats. J Am Heart Assoc, 8(1):e010418.

[42]ShiXY, XiongLX, XiaoL, et al., 2016. Downregulation of caveolin-1 upregulates the expression of growth factors and regulators in co-culture of fibroblasts with cancer cells. Mol Med Rep, 13(1):744-752.

[43]ShihataWA, PutraMRA, Chin-DustingJPF, 2017. Is there a potential therapeutic role for caveolin-1 in fibrosis? Front Pharmacol, 8:567.

[44]ShimizuI, MinaminoT, 2016. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol, 97:245-262.

[45]ShindoT, ItoK, OgataT, et al., 2016. Low-intensity pulsed ultrasound enhances angiogenesis and ameliorates left ventricular dysfunction in a mouse model of acute myocardial infarction. Arterioscler Thromb Vasc Biol, 36(6):1220-1229.

[46]SwärdK, AlbinssonS, RippeC, 2014. Arterial dysfunction but maintained systemic blood pressure in cavin-1-deficient mice. PLoS ONE, 9(3):e92428.

[47]SweeneyM, CordenB, CookSA, 2020. Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle? EMBO Mol Med, 12(10):e10865.

[48]TallquistMD, 2020. Cardiac fibroblast diversity. Annu Rev Physiol, 82:63-78.

[49]VandergriffAC, VandergriffMT, ChengK, 2015. Isolation and cryopreservation of neonatal rat cardiomyocytes. J Vis Exp, 9(98):52726.

[50]VogelER, ManloveLJ, KuipersI, et al., 2019. Caveolin-1 scaffolding domain peptide prevents hyperoxia-induced airway remodeling in a neonatal mouse model. Am J Physiol Lung Cell Mol Physiol, 317(1):L99-L108.

[51]VolonteD, GalbiatiF, 2020. Caveolin-1, a master regulator of cellular senescence. Cancer Metastasis Rev, 39(2):397-414.

[52]WangJX, ChenHJ, CaoP, et al., 2016. Inflammatory cytokines induce caveolin-1/β-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway. Cell Prolif, 49(3):362-372.

[53]WangQ, YuY, ZhangPP, et al., 2017. The crucial role of activin A/ALK4 pathway in the pathogenesis of Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation. Basic Res Cardiol, 112(4):47.

[54]XuTH, ZhaoK, GuoXS, et al., 2019. Low-intensity pulsed ultrasound inhibits adipogenic differentiation via HDAC1 signalling in rat visceral preadipocytes. Adipocyte, 8(1):292-303.

[55]YanHL, LiYF, WangC, et al., 2017. Contrary microRNA expression pattern between fetal and adult cardiac remodeling: therapeutic value for heart failure. Cardiovasc Toxicol, 17(3):267-276.

[56]ZaragozaC, SauraM, Ramírez-CarracedoR, 2021. Cardiac microvasculature and adverse remodeling after acute myocardial infarction. New evidence on the use of VEGF as a therapeutic target. Rev Esp Cardiol (Engl Ed), 74(2):124-125.

[57]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.

[58]ZhaoK, WengLQ, XuTH, et al., 2021. Low-intensity pulsed ultrasound prevents prolonged hypoxia-induced cardiac fibrosis through HIF-1α/DNMT3a pathway via a TRAAK-dependent manner. Clin Exp Pharmacol Physiol, early access.

[59]ZhaoY, LiuK, YinD, et al., 2019. Angiopoietin-like 7 contributes to angiotensin II-induced proliferation, inflammation and apoptosis in vascular smooth muscle cells. Pharmacology, 104(5-6):226-234.

[60]ZhengC, WuSM, LianH, et al., 2019. Low-intensity pulsed ultrasound attenuates cardiac inflammation of CVB3-induced viral myocarditis via regulation of caveolin-1 and MAPK pathways. J Cell Mol Med, 23(3):1963-1975.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

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 - 2022 Journal of Zhejiang University-SCIENCE