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Updated: Oct 13, 2025
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
SUR1-E1506K mutation impairs glucose tolerance and promotes vulnerable atherosclerotic plaque phenotype in
Erika Gurzeler1, Anna-Kaisa Ruotsalainen1, Anssi Laine1
1A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
Insights
The SUR1-E1506K mutation worsens atherosclerosis in mice by impairing glucose tolerance and increasing arterial inflammation, leading to more vulnerable plaques. This highlights a link between diabetes risk factors and cardiovascular disease progression.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Genetic Mutation Impact Studies
Background:
- Diabetes mellitus is a significant risk factor for atherosclerosis.
- The sulfonylurea receptor 1 (SUR1) E1506K mutation causes hyperinsulinemia and increases type 2 diabetes risk.
- Investigating the SUR1-E1506K mutation's role in atherosclerosis is crucial for understanding diabetes complications.
Purpose of the Study:
- To determine the effect of the SUR1-E1506K mutation on atherogenesis.
- To analyze plaque morphology and vulnerability in a mouse model.
- To assess glucose metabolism and arterial inflammation associated with the mutation.
Main Methods:
- Cross-breeding SUR1-E1506K mutated mice with LDLR-/- mice.
- Feeding a Western diet to induce atherosclerosis in 6-month-old mice for 6 months.
- Analyzing atherosclerotic plaque characteristics, glucose metabolism, and inflammatory markers (IL-1β, NLRP3, IL-18).
Main Results:
- SUR1Δ/LDLR-/- mice showed increased plaque necrotic area and reduced smooth muscle cells, indicating higher vulnerability.
- Impaired glucose tolerance and elevated fasting glucose were observed in SUR1Δ/LDLR-/- mice post-diet.
- Increased IL-1β, NLRP3 inflammasome, and IL-18 levels were found in aortic sections and macrophages of SUR1Δ/LDLR-/- mice.
Conclusions:
- The SUR1-E1506K mutation exacerbates atherosclerosis by promoting a vulnerable plaque phenotype.
- Impaired glucose tolerance and heightened arterial inflammation are key consequences of the mutation.
- This study links specific genetic mutations related to diabetes to adverse cardiovascular outcomes.
Background And Aims:
Diabetes is a major risk factor of atherosclerosis and its complications. The loss-of-function mutation E1506K in the sulfonylurea receptor 1 (SUR1-E1506K) induces hyperinsulinemia in infancy, leading to impaired glucose tolerance and increased risk of type 2 diabetes. In this study, we investigate the effect of SUR1-E1506K mutation on atherogenesis in hypercholesterolemic LDLR-/- mice.
Methods:
SUR1-E1506K mutated mice were cross-bred with LDLR-/- mice (SUR1Δ/LDLR-/-), 6 months old mice were fed a western-diet (WD) for 6 months to induce advanced atherosclerotic plaques. At the age of 12 months, atherosclerosis and plaque morphology were analyzed and mRNA gene expression were measured from aortic sections and macrophages. Glucose metabolism was characterized before and after WD. Results were compared to age-matched LDLR-/- mice.
Results:
Advanced atherosclerotic plaques did not differ in size between the two strains. However, in SUR1Δ/LDLR-/- mice, plaque necrotic area was increased and smooth muscle cell number was reduced, resulting in higher plaque vulnerability index in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice. SUR1Δ/LDLR-/- mice exhibited impaired glucose tolerance and elevated fasting glucose after WD. The positive staining area of IL-1β and NLRP3 inflammasome were increased in aortic sections in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice, and IL-18 plasma level was elevated in SUR1Δ/LDLR-/- mice. Finally, the mRNA expression of IL-1β and IL-18 were increased in SUR1Δ/LDLR-/- bone marrow derived macrophages in comparison to LDLR-/- macrophages in response to LPS.
Conclusions:
SUR1-E1506K mutation impairs glucose tolerance and increases arterial inflammation, which promotes a vulnerable atherosclerotic plaque phenotype in LDLR-/- mice.
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