Inhibition of Intimal Thickening By PRH (Proline-Rich Homeodomain) in Mice

Lien Mari P. Reolizo, Helen Williams, A Frankow, Ze Li, Kevin L Gaston, Padma-Sheela Jayaraman, Jason L Johnson, Sarah J George*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)

Abstract

Objective:
Late vein graft failure is caused by intimal thickening resulting from endothelial cell (EC) damage and inflammation which promotes vascular smooth muscle cell (VSMC) de-differentiation, migration, and proliferation. Non-phosphorylatable PRH S163C:S177C offers enhanced stability and sustained anti-mitotic effect. Therefore, we investigated whether adenovirus-delivered of PRH S163C:S177C protein attenuates intimal thickening via VSMC phenotype modification without detrimental effects on ECs.

Approach and Results:
PRH S163C:S177C expression in human saphenous vein (HSV)-VSMCs inhibited proliferation, migration and apoptosis compared to virus control. Western blotting revealed that PRH S163C:S177C enhanced contractile filament proteins and enhanced collagen-gel contraction in HSV-VSMCs. Importantly, PRH S163C:S177C expression in HSV-ECs significantly reduced apoptosis, without affecting cell proliferation and migration compared to control virus. PRH S163C:S177C reduced TNF-α-induced VCAM-1 and ICAM-1 and monocyte adhesion in HSV-ECs and suppressed interleukin-6 and monocyte chemotactic factor-1 protein levels. Local delivery of PRH S163C:S177C to ligated murine carotid-arteries significantly impaired carotid artery ligation-induced neointimal proliferation and thickening without reducing endothelial coverage. Next Generation Sequencing revealed signal transducer and activator of transcription 1 (STAT-1) and histone deacetylase 9 (HDAC-9) as novel downstream mediators of PRH action and this was supported by in vitro and in vivo analyses.

Conclusion:
We observed that PRH S163C:S177C attenuated VSMC proliferation, and migration and enhanced VSMC differentiation at least in part via STAT-1 and HDAC-9 signalling, whilst promoting endothelial repair and anti-inflammatory properties. These novel findings highlight the potential for PRH S163C:S177C to preserve endothelial function whilst suppressing intimal thickening, and thereby reduce late vein graft failure.
Original languageEnglish
Pages (from-to)456-473
Number of pages18
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume43
Issue number3
Early online date26 Jan 2023
DOIs
Publication statusE-pub ahead of print - 26 Jan 2023

Bibliographical note

Funding Information:
This work was supported by the British Heart Foundation (FS/17/46/33121).

Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.

Structured keywords

  • Bristol Heart Institute

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