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Published on: September 26, 2018
IL-1β Inhibition Partially Negates the Beneficial Effects of Diet-Induced Atherosclerosis Regression in Mice
Santosh Karnewar1, Vaishnavi Karnewar1, Rebecca A Deaton1
1Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (S. Karnewar, V.K., R.A.D., L.S.S., C.M.W., X.B., G.F.A., G.B.B., S. Kirmani, R.A.B., E.R.Z., G.K.O.).
Insights
Lipid lowering reduces atherosclerotic plaque burden. However, Interleukin-1 beta (IL-1β) antibody treatment unexpectedly worsened plaque stability and increased lesion size in mice, suggesting IL-1β is crucial for maintaining diet-induced plaque improvements.
Area of Science:
- Cardiovascular Research
- Immunology
- Atherosclerosis Research
Background:
- Advanced atherosclerotic lesions cause major adverse cardiovascular events like heart attack and stroke.
- Aggressive lipid lowering is key to reducing cardiovascular events, but its effects on plaque stability are unclear.
- Understanding how lipid reduction impacts atherosclerotic plaque composition and stability is vital for developing better therapies.
Purpose of the Study:
- To investigate the effects of dietary lipid reduction on atherosclerotic plaque composition and stability.
- To explore the role of Interleukin-1 beta (IL-1β) in modulating plaque stability during lipid lowering.
- To identify therapeutic strategies that enhance the benefits of lipid-lowering interventions.
Main Methods:
- Apoe-/- mice on a high-cholesterol diet were switched to a standard diet to lower lipids.
- Mice were subsequently treated with an IL-1β antibody or control antibody.
- Lesion size, plaque stability indices, cellular composition, and cell phenotypic transitions were analyzed using advanced techniques including single-cell RNA sequencing.
Main Results:
- Diet-induced lipid lowering reduced LDL cholesterol, aortic plaque burden, intraplaque hemorrhage, and necrotic core area.
- IL-1β antibody treatment paradoxically increased plaque burden, lesion size, intraplaque hemorrhage, necrotic core area, and senescence.
- IL-1β antibody treatment altered inflammatory and extracellular matrix pathways, negatively impacting plaque stability.
Conclusions:
- IL-1β is essential for maintaining diet-induced reductions in atherosclerotic plaque burden.
- IL-1β plays a critical role in enhancing plaque stability following lipid-lowering interventions.
- Targeting IL-1β may be a potential therapeutic strategy to improve outcomes in atherosclerosis management.
Background:
Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions is the global leading cause of death. The most common and effective means to reduce these major adverse cardiovascular events, including myocardial infarction and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, we know little regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering.
Methods:
Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1β or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis.
Results:
Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1β antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1β antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap.
Conclusions:
Taken together, IL-1β appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.
