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Published on: September 26, 2018
A novel RANTES antagonist prevents progression of established atherosclerotic lesions in mice
Vincent Braunersreuther1, Sabine Steffens, Claire Arnaud
1Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Researches, 64 Avenue Roseraie, 1211 Geneva, Switzerland.
Insights
A novel chemokine variant, [44AANA47]-RANTES, effectively limits atherosclerosis progression in mice by reducing inflammatory cell recruitment. This approach stabilizes plaques and decreases the overall inflammatory state.
Area of Science:
- Cardiovascular Research
- Immunology
- Molecular Biology
Background:
- Atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the endothelium.
- Chemokines are key mediators of this inflammatory cell infiltration.
- A specific chemokine variant, [44AANA47]-RANTES, interferes with chemokine function by disrupting heparin binding and oligomerization.
Purpose of the Study:
- To investigate the therapeutic potential of [44AANA47]-RANTES in established atherosclerosis.
- To determine the effects of [44AANA47]-RANTES on inflammatory cell infiltration and plaque stability in a mouse model.
Main Methods:
- Treatment of LDLr-/- mice with [44AANA47]-RANTES.
- Assessment of atherosclerotic plaque formation, immune cell infiltration (T cells, macrophages), and matrix metalloproteinase-9 (MMP-9) production.
- Analysis of plaque composition, including smooth muscle cell and collagen content.
- In vivo evaluation of leukocyte rolling and arrest in mesenteric vessels.
- In vitro assessment of pro-inflammatory responses following Concanavalin A (Con A) stimulation.
Main Results:
- Curative treatment with [44AANA47]-RANTES significantly limited atherosclerotic plaque formation.
- Reduced infiltration of T cells and macrophages, along with decreased MMP-9 production, was observed.
- Increased smooth muscle cell and collagen content indicated a more stable plaque phenotype.
- Direct inhibition of leukocyte recruitment into aortic root lesions and attenuated leukocyte rolling/arrest in mesenteric vessels were demonstrated.
- A reduced pro-inflammatory response was noted following Con A stimulation in vitro.
Conclusions:
- Interfering with chemokine oligomerization and heparin interactions, as exemplified by [44AANA47]-RANTES, is a viable strategy to inhibit atherosclerosis progression.
- [44AANA47]-RANTES effectively reduces leukocyte recruitment into plaques, leading to a less inflammatory phenotype and a reduced systemic inflammatory state.
Background:
Atherosclerosis is a chronic inflammatory disease that represents the primary cause of death through coronary disease and stroke. Chemokines are known to play a crucial role in this disease by recruiting inflammatory leukocytes to the endothelium. Recently, the chemokine variant [44AANA47]-RANTES was shown to impair inflammatory cell recruitment in vivo by interfering with heparin binding and oligomerization.
Methods And Results:
In this study we report that curative treatment with [44AANA47]-RANTES limits atherosclerotic plaque formation in LDLr-/- mice. This was associated with reduced infiltration of T cells and macrophages and reduced production of matrix metalloproteinase (MMP)-9. By contrast, the relative smooth muscle cell and collagen content was increased, indicating a more stable plaque phenotype. In addition, we provide evidence for direct inhibition of leukocyte recruitment into aortic root lesions, attenuated leukocyte rolling and arrest in mesenteric vessels, as well as a reduced proinflammatory response following Con A stimulation in vitro.
Conclusions:
Interference with chemokine oligomerization and chemokine/heparin interactions is a powerful novel approach that inhibits progression of established atherosclerosis in mice. By inhibiting leukocyte recruitment into plaques, [44AANA47]-RANTES mediates a less inflammatory plaque phenotype and thus reduced systemic inflammatory state.
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