Inhibition of HDAC6 Activity Protects Against Endothelial Dysfunction and Atherogenesis in vivo: A Role for HDAC6 Neddylation

被引:16
作者
Nomura, Yohei [1 ,2 ]
Nakano, Mitsunori [1 ,2 ]
Woo Sung, Hyun [3 ]
Han, Mingming [1 ,4 ]
Pandey, Deepesh [1 ]
机构
[1] Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21218 USA
[2] Jichi Med Univ, Saitama Med Ctr, Dept Cardiovasc Surg, Saitama, Japan
[3] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD USA
[4] Univ Sci & Technol China, Affiliated Hosp USTC 1, Dept Anesthesiol, Hefei, Peoples R China
来源
FRONTIERS IN PHYSIOLOGY | 2021年 / 12卷
基金
美国国家卫生研究院;
关键词
endothelial (dys)function; vascular biology; atherosclerosis; epigentic modifier; epigenetic regulator; LOW-DENSITY-LIPOPROTEIN; HISTONE-DEACETYLASE; ATHEROSCLEROSIS; CELLS; INFLAMMATION; ACETYLATION; ACTIVATION; RELAXATION; IMPAIRMENT; APOPTOSIS;
D O I
10.3389/fphys.2021.675724
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
We previously reported that histone deacetylase 6 (HDAC6) has an important role in endothelial cell (EC) function in vitro. However, whether HDAC6 plays a role in atherogenesis in vivo and the mechanism(s) that control HDAC6 activity/expression in response to atherogenic stimuli are unclear. The goals of this study were to determine whether HDAC6 inhibitor tubacin attenuates atherogenesis and to elucidate specific molecular mechanism(s) that regulate endothelial HDAC6 expression/activity. We evaluated whether administration of tubacin attenuated or reversed the endothelial dysfunction and atherosclerosis induced in mice by a single intraperitoneal injection of adeno-associated viruses encoding liver-target PCSK9 gain-of-function mutant followed by a high fat diet (HFD) for 18 weeks. Tubacin significantly blunted PCSK9-induced increases in pulse wave velocity (index of vascular stiffness and overall vascular health) that are also seen in atherogenic mice. Furthermore, tubacin protected vessels from defective vasorelaxation, as evaluated by acetylcholine-mediated relaxation using wire myograph. Plaque burden defined by Oil Red O staining was also found to be significantly less in mice that received tubacin than in those that received PCSK9 alone. Inhibition of the NEDDylation pathway with MLN4924, an inhibitor of NEDD8-activating enzyme 1 (NAE1), significantly increased HDAC6 activity in HAECs. Interestingly, HDAC6 expression remained unchanged. Further, HAECs exposed to the atherogenic stimulus oxidized low-density lipoprotein (OxLDL) exhibited enhanced HDAC6 activity, which was attenuated by pretreatment with MLN4924. The HDAC6 NEDDylation molecular pathway might regulate genes related to endothelial control of vasomotor tone, reactivity, and atherosclerosis. Tubacin may represent a novel pharmacologic intervention for atherogenesis and other vasculopathies.
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页数:10
相关论文
共 43 条
  • [1] Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo
    Asare, Yaw
    Ommer, Miriam
    Azombo, Florence. A.
    Alampour-Rajabi, Setareh
    Sternkopf, Marieke
    Sanati, Maryam
    Gijbels, Marion J.
    Schmitz, Corinna
    Sinitski, Dzmitry
    Tilstam, Pathricia V.
    Lue, Hongqi
    Gessner, Andre
    Lange, Denise
    Schmid, Johannes A.
    Weber, Christian
    Dichgans, Martin
    Jankowski, Joachim
    Pardi, Ruggero
    de Winther, Menno P. J.
    Noels, Heidi
    Bernhagen, Juergen
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2017, 114 (13) : E2766 - E2775
  • [2] HDAC6-p97/VCP controlled polyubiquitin chain turnover
    Boyault, Cyril
    Gilquin, Benoit
    Zhang, Yu
    Rybin, Vladimir
    Garman, Elspeth
    Meyer-Klaucke, Wolfram
    Matthias, Patrick
    Muller, Christoph W.
    Khochbin, Saadi
    [J]. EMBO JOURNAL, 2006, 25 (14) : 3357 - 3366
  • [3] Inhibition of Neddylation Represses Lipopolysaccharide-induced Proinflammatory Cytokine Production in Macrophage Cells
    Chang, Fang-Mei
    Reyna, Sara M.
    Granados, Jose C.
    Wei, Sung-Jen
    Innis-Whitehouse, Wendy
    Maffi, Shivani K.
    Rodriguez, Edward
    Slaga, Thomas J.
    Short, John D.
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (42) : 35756 - 35767
  • [4] The histone deacetylase inhibitor tubacin mitigates endothelial dysfunction by up-regulating the expression of endothelial nitric oxide synthase
    Chen, Jihui
    Zhang, Jian
    Shaik, Noor F.
    Yi, Bing
    Wei, Xin
    Yang, Xiao-Feng
    Naik, Ulhas P.
    Summer, Ross
    Yan, Guijun
    Xu, Xinyun
    Sun, Jianxin
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2019, 294 (51) : 19565 - 19576
  • [5] Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice
    Choi, JH
    Nam, KH
    Kim, J
    Baek, MW
    Park, JE
    Park, HY
    Kwon, HJ
    Kwon, OS
    Kim, DY
    Oh, GT
    [J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (11) : 2404 - 2409
  • [6] Dimmeler S, 1997, CIRCULATION, V95, P1760
  • [7] Central Role for Endothelial Human Deneddylase-1/SENP8 in Fine-Tuning the Vascular Inflammatory Response
    Ehrentraut, Stefan F.
    Kominsky, Douglas J.
    Glover, Louise E.
    Campbell, Eric L.
    Kelly, Caleb J.
    Bowers, Brittelle E.
    Bayless, Amanda J.
    Colgan, Sean P.
    [J]. JOURNAL OF IMMUNOLOGY, 2013, 190 (01) : 392 - 400
  • [8] Protein neddylation: beyond cullin-RING ligases
    Enchev, Radoslav I.
    Schulman, Brenda A.
    Peter, Matthias
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2015, 16 (01) : 30 - 44
  • [9] IMPAIRMENT OF ENDOTHELIUM-DEPENDENT DILATION IN RABBIT RENAL-ARTERIES BY OXIDIZED LIPOPROTEIN(A) - ROLE OF OXYGEN-DERIVED RADICALS
    GALLE, J
    BENGEN, J
    SCHOLLMEYER, P
    WANNER, C
    [J]. CIRCULATION, 1995, 92 (06) : 1582 - 1589
  • [10] A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification
    Goettsch, Claudia
    Hutcheson, Joshua D.
    Hagita, Sumihiko
    Rogers, Maximillian A.
    Creager, Michael D.
    Tan Pham
    Choi, Jung
    Mlynarchik, Andrew K.
    Pieper, Brett
    Kjolby, Mads
    Aikawa, Masanori
    Aikawa, Elena
    [J]. ATHEROSCLEROSIS, 2016, 251 : 109 - 118