Abstract
Background and aimsDiabetes 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.MethodsSUR1-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.ResultsAdvanced 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.ConclusionsSUR1-E1506K mutation impairs glucose tolerance and increases arterial inflammation, which promotes a vulnerable atherosclerotic plaque phenotype in LDLR-/- mice.
Highlights
Type 2 diabetes mellitus and its complications are increasing worldwide, leading to death and reduced quality of life in a large number of patients [1, 2]
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
The expression of pro-inflammatory cytokine IL-1β and NLRP3 inflammasome were increased in aortic sections in SUR1Δ/LDLR-/- mice, suggesting that impaired glucose metabolism promotes plaque vulnerability via increased arterial wall inflammation in SUR1Δ/LDLR-/- mice
Summary
Type 2 diabetes mellitus and its complications are increasing worldwide, leading to death and reduced quality of life in a large number of patients [1, 2]. Atherosclerosis is a chronic inflammatory disease, defined by accumulation of lipids, lipoproteins, smooth muscle cells, connective tissue and inflammatory cells in the intimal layer of the arterial wall causing the formation of atherosclerotic plaques [5]. Atherosclerosis develops through LDL retention and its modifications in the intima [7], attracting macrophages that engulf modified LDL and form foam cells and fatty streaks [8] This accumulation of lipids and macrophage foam cells provoke local vascular cytokine secretion and increase the expression of chemotactic proteins and adhesion molecules, promoting accumulation of inflammatory cells [9, 10]. We investigate the effect of SUR1-E1506K mutation on atherogenesis in hypercholesterolemic LDLR-/- mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
