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Published on: August 20, 2019
Cytoprotective signaling and gene expression in endothelial cells and macrophages-lessons for atherosclerosis
Dorian O Haskard1, Joseph J Boyle, Paul C Evans
1Vascular Science Section, National Heart and Lung Institute, Imperial College, Hammersmith Hospital, London W12 ONN, UK. d.haskard@imperial.ac.uk
Insights
This review explores how signaling pathways influence gene expression in atherosclerosis, focusing on protective responses. Understanding these mechanisms could lead to new therapeutic strategies for this chronic inflammatory disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Inflammation Research
Background:
- Atherosclerosis is a chronic inflammatory arterial disease.
- Oxidized low-density lipoproteins and debris accumulate in susceptible arterial sites.
- Pathologic microcirculation in lesions drives disease progression via immune cell recruitment and micro-hemorrhage.
Purpose of the Study:
- To review research on signaling pathways governing gene expression in atherosclerosis.
- To highlight cytoprotective responses that may be therapeutically enhanced.
- To explore both transcriptional and post-transcriptional regulatory mechanisms.
Main Methods:
- Investigated roles of signaling pathways in atherosclerotic gene expression.
- Examined anti-inflammatory effects of arterial laminar shear stress.
- Studied mechanisms of membrane inhibitor induction and homeostatic macrophage responses.
Main Results:
- Signaling pathways orchestrate gene expression programs in the atherosclerotic environment.
- Arterial shear stress exhibits anti-inflammatory effects.
- Mechanisms controlling endothelial cell stability, survival, and quiescence were elucidated.
Conclusions:
- Therapeutic enhancement of cytoprotective responses is a promising avenue for atherosclerosis treatment.
- Both transcriptional and post-transcriptional regulation are crucial for fine-tuning gene expression in atherosclerosis.
- Further research into these regulatory mechanisms can advance atherosclerosis therapy.
Abstract:
Atherosclerosis is a chronic inflammatory disease of the medium and large arteries driven in large part by the accumulation of oxidized low-density lipoproteins and other debris at sites rendered susceptible because of the geometry of the arterial tree. As lesions develop, they acquire a pathologic microcirculation that perpetuates lesion progression, both by providing a means for further monocyte and T-lymphocyte recruitment into the arterial wall and by the physical and chemical stresses caused by micro-hemorrhage. This review summarizes work performed in our department investigating the roles of signaling pathways, alone and in combination, that lead to specific programs of gene expression in the atherosclerotic environment. Focusing particularly on cytoprotective responses that might be enhanced therapeutically, the work has encompassed the anti-inflammatory effects of arterial laminar shear stress, mechanisms of induction of membrane inhibitors that prevent complement-mediated injury, homeostatic macrophage responses to hemorrhage, and the transcriptional mechanisms that control the stability, survival, and quiescence of endothelial monolayers. Lastly, while the field has been dominated by investigation into the mechanisms of DNA transcription, we consider the importance of parallel post-transcriptional regulatory mechanisms for fine-tuning functional gene expression repertoires.
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