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.
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 language | English |
|---|---|
| Pages (from-to) | 456-473 |
| Number of pages | 18 |
| Journal | Arteriosclerosis, Thrombosis, and Vascular Biology |
| Volume | 43 |
| Issue number | 3 |
| Early online date | 26 Jan 2023 |
| DOIs | |
| Publication status | E-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.
Research Groups and Themes
- Bristol Heart Institute
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