Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitor

被引:6
|
作者
Nukala, Sarath Babu [1 ]
Jousma, Jordan [1 ]
Yan, Gege [1 ]
Han, Zhenbo [1 ]
Kwon, Youjeong [1 ]
Cho, Yoonje [1 ]
Liu, Chuyu [2 ]
Gagnon, Keith [3 ,4 ]
Pinho, Sandra [1 ]
Rehman, Jalees [1 ,5 ]
Shao, Ning-Yi [2 ]
Ong, Sang-Bing [6 ,7 ,8 ,9 ]
Lee, Won Hee [10 ]
Ong, Sang-Ging [1 ,6 ]
机构
[1] Univ Illinois, Coll Med, Dept Pharmacol & Regenerat Med, 909 S Wolcott Ave, Chicago, IL 60607 USA
[2] Univ Macau, Fac Hlth Sci, Ave Univ, Macau 999078, Peoples R China
[3] Southern Illinois Univ, Sch Med, Div Biochem & Mol Biol, 1245 Lincoln Dr, Carbondale, IL 62901 USA
[4] Southern Illinois Univ, Dept Chem & Biochem, 1245 Lincoln Dr, Carbondale, IL 62901 USA
[5] Univ Illinois, Coll Med, Dept Med, Div Cardiol, 840 S Wood St, Chicago, IL 60612 USA
[6] Chinese Univ Hong Kong CUHK, Prince Wales Hosp, Fac Med, Dept Med & Therapeut,Shatin, 9-F, Lui Che Woo Clin Sci Bldg, Hong Kong, Peoples R China
[7] Prince Wales Hosp, Lui Che Woo Inst Innovat Med, Ctr Cardiovasc Genom & Med CCGM, Shatin, 10-F, Lui Che Woo Clin Sci Bldg, Hong Kong, Peoples R China
[8] Hong Kong Childrens Hosp HKCH, Hong Kong Hub Paediat Excellence HK HOPE, Kowloon Bay, 8-F, Tower, 1 Shing Cheong Rd, Hong Kong, Peoples R China
[9] Chinese Univ Hong Kong KIZ CUHK, Chinese Acad Sci, Kunming Inst Zool, Joint Lab Bioresources & Mol Res Common Dis, Kunming, Yunnan, Peoples R China
[10] Univ Arizona, Coll Med, Dept Basic Med Sci, 425 North 5th St, Phoenix, AZ 85004 USA
基金
美国国家卫生研究院;
关键词
iPSCs; Cardio-oncology; Vascular toxicity; lncRNAs; Glycocalyx; SUNITINIB-INDUCED CARDIOTOXICITY; CANCER-THERAPIES; IN-VIVO; CELL; CARDIOMYOCYTE; DEGRADATION; TOXICITIES; IMPAIRMENT; DISEASE; TARGET;
D O I
10.1093/cvr/cvad087
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aims Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi-receptor tyrosine kinase inhibitor, has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and results We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human-induced pluripotent stem cell-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to down-regulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirmed that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and up-regulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in Has2os and degradation of the endothelial glycocalyx. Finally, we identified that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
引用
收藏
页码:1997 / 2013
页数:17
相关论文
共 50 条
  • [31] Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors
    Wulkersdorfer, Beatrix
    Zeitlinger, Markus
    Schmid, Monika
    CLINICAL PHARMACOKINETICS, 2016, 55 (01) : 47 - 77
  • [32] Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors
    Roy, Bhaskar
    Das, Avash
    Ashish, Kumar
    Bandyopadhyay, Dhrubajyoti
    Maiti, Abhishek
    Chakraborty, Sandipan
    Stone, Martha E.
    Philpotts, Lisa Liang
    Nowak, Richard J.
    Patwa, Huned S.
    NEUROLOGY, 2019, 93 (02) : E143 - E148
  • [33] Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors
    Beatrix Wulkersdorfer
    Markus Zeitlinger
    Monika Schmid
    Clinical Pharmacokinetics, 2016, 55 : 47 - 77
  • [34] Pancreatitis with vascular endothelial growth factor receptor tyrosine kinase inhibitors
    Ghatalia, Pooja
    Morgan, Charity J.
    Choueiri, Toni K.
    Rocha, Pedro
    Naik, Gurudatta
    Sonpavde, Guru
    CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, 2015, 94 (01) : 136 - 145
  • [35] Effects of interleukin 6 inhibitor tocilizumab on endothelial glycocalyx, vascular and myocardial function compared to prednisolone
    Ikonomidis, I.
    Pavlidis, G.
    Katsimbri, P.
    Andreadou, I.
    Triantafyllidi, H.
    Tsoumani, M.
    Varoudi, M.
    Thymis, I.
    Triantafyllou, C.
    Kostelli, G.
    Frogoudaki, A.
    Vrettou, A. R.
    Boumpas, D.
    Alexopoulos, D.
    Iliodromitis, E.
    EUROPEAN HEART JOURNAL, 2019, 40 : 2665 - 2665
  • [36] Vascular endothelial cells express isoforms of protein kinase A inhibitor
    Lum, H
    Hao, ZP
    Gayle, D
    Kumar, P
    Patterson, CE
    Uhler, MD
    AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2002, 282 (01): : C59 - C66
  • [37] SU-011248, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor, controls chronic psoriasis
    Keshtgarpour, Mani
    Dudek, Arkadiusz Z.
    TRANSLATIONAL RESEARCH, 2007, 149 (03) : 103 - 106
  • [38] Expression and purification of human vascular-endothelial-growth-factor-receptor-2 tyrosine kinase in Streptomyces for inhibitor screening
    Liu, Chunping
    Guo, Lianhong
    Yao, Chen
    Zhang, Ren
    Li, Yuan
    BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY, 2008, 50 : 113 - 119
  • [39] ZM323881, a novel inhibitor of vascular endothelial growth factor-receptor-2 tyrosine kinase activity
    Whittles, CE
    Pocock, TM
    Wedge, SR
    Kendrew, J
    Hennequin, LF
    Harper, SJ
    Bates, DO
    MICROCIRCULATION, 2002, 9 (06) : 513 - 522
  • [40] Fulminant Vascular and Cardiac Toxicity Associated with Tyrosine Kinase Inhibitor Sorafenib
    Sudasena, Daryl
    Balanescu, Dinu Valentin
    Donisan, Teodora
    Hassan, Saamir
    Palaskas, Nicolas
    Kim, Peter
    Karimzad, Kaveh
    Lopez-Mattei, Juan
    Arain, Salman
    Gould, K. Lance
    Iliescu, Cezar
    CARDIOVASCULAR TOXICOLOGY, 2019, 19 (04) : 382 - 387