Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype

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DOI

  • Laura Lecce, Icahn School of Medicine at Mount Sinai
  • ,
  • Yang Xu, Icahn School of Medicine at Mount Sinai
  • ,
  • Bhargavi V'Gangula, Icahn School of Medicine at Mount Sinai
  • ,
  • Nirupama Chandel, Icahn School of Medicine at Mount Sinai
  • ,
  • Venu Pothula, Icahn School of Medicine at Mount Sinai
  • ,
  • Axelle Caudrillier, University of Edinburgh
  • ,
  • Maria Paola Santini, Icahn School of Medicine at Mount Sinai
  • ,
  • Valentina D'Escamard, Icahn School of Medicine at Mount Sinai
  • ,
  • Delaine K. Ceholski, Icahn School of Medicine at Mount Sinai
  • ,
  • Przemek A. Gorski, Icahn School of Medicine at Mount Sinai
  • ,
  • Lijiang Ma, Icahn School of Medicine at Mount Sinai
  • ,
  • Simon Koplev, Icahn School of Medicine at Mount Sinai
  • ,
  • Martin Mæng Bjørklund
  • Johan L.M. Björkegren, Icahn School of Medicine at Mount Sinai, Karolinska Institutet
  • ,
  • Manfred Boehm, National Institutes of Health
  • ,
  • Jacob Fog Bentzon
  • Valentin Fuster, Icahn School of Medicine at Mount Sinai, Instituto de Salud Carlos III
  • ,
  • Ha Won Kim, Augusta University
  • ,
  • Neal L. Weintraub, Augusta University
  • ,
  • Andrew H. Baker, University of Edinburgh
  • ,
  • Emily Bernstein, Icahn School of Medicine at Mount Sinai
  • ,
  • Jason C. Kovacic, Icahn School of Medicine at Mount Sinai, Victor Chang Cardiac Research Institute, University of New South Wales

Endothelial-mesenchymal transition (EndMT) is associated with various cardiovascular diseases and in particular with atherosclerosis and plaque instability. However, the molecular pathways that govern EndMT are poorly defined. Specifically, the role of epigenetic factors and histone deacetylases (HDACs) in controlling EndMT and the atherosclerotic plaque phenotype remains unclear. Here, we identified histone deacetylation, specifically that mediated by HDAC9 (a class IIa HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, we found class IIa HDAC inhibition sustained the expression of endothelial proteins and mitigated the increase in mesenchymal proteins, effectively blocking EndMT. Similarly, ex vivo genetic knockout of Hdac9 in endothelial cells prevented EndMT and preserved a more endothelial-like phenotype. In vivo, atherosclerosis-prone mice with endothelial-specific Hdac9 knockout showed reduced EndMT and significantly reduced plaque area. Furthermore, these mice displayed a more favorable plaque phenotype, with reduced plaque lipid content and increased fibrous cap thickness. Together, these findings indicate that HDAC9 contributes to vascular pathology by promoting EndMT. Our study provides evidence for a pathological link among EndMT, HDAC9, and atherosclerosis and suggests that targeting of HDAC9 may be beneficial for plaque stabilization or slowing the progression of atherosclerotic disease.

OriginalsprogEngelsk
Artikelnummere131178
TidsskriftJournal of Clinical Investigation
Vol/bind131
Nummer15
ISSN0021-9738
DOI
StatusUdgivet - aug. 2021

Bibliografisk note

Funding Information:
This study was directly supported by NIH grant R01HL130423. Confocal microscopy was performed at the Microscopy CoRE and flow cytometry at the Flow Cytometry CoRE of the Icahn School of Medicine at Mount Sinai. JCK acknowledges support from the NIH (R01HL130423, R01HL135093, R01HL148167). YX was supported by a generous gift from the Haver Foundation and Maurine Haver. NC and VDE were supported by NIH grant T32HL007824. PAG was supported by a Canadian Institutes of Health Research postdoctoral fellowship. JLMB acknowledges support from Astra-Zeneca, NIH R01HL125863, and the Fon-dation Leducq. NLW is supported by HL142097, HL134354, HL126949, and AR070029. The CNIC is supported by the Insti-tuto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Inno-vación (MCIN), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). AHB is supported by the BHF Chair of Translational Cardiovascular Sciences and grants RG/14/3/30706 and ERC Advanced Grant VASCMIR. EB acknowledges support from NIH R01CA154683.

Funding Information:
This study was directly supported by NIH grant R01HL130423. Confocal microscopy was performed at the Microscopy CoRE and flow cytometry at the Flow Cytometry CoRE of the Icahn School of Medicine at Mount Sinai. JCK acknowledges support from the NIH (R01HL130423, R01HL135093, R01HL148167). YX was supported by a generous gift from the Haver Foundation and Maurine Haver. NC and VDE were supported by NIH grant T32HL007824. PAG was supported by a Canadian Institutes of Health Research postdoctoral fellowship. JLMB acknowledges support from Astra-Zeneca, NIH R01HL125863, and the Fondation Leducq. NLW is supported by HL142097, HL134354, HL126949, and AR070029. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovaci?n (MCIN), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). AHB is supported by the BHF Chair of Translational Cardiovascular Sciences and grants RG/14/3/30706 and ERC Advanced Grant VASCMIR. EB acknowledges support from NIH R01CA154683.

Publisher Copyright:
© 2021, Lecce et al.

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