Type 1 diabetes promotes disruption of advanced atherosclerotic lesions in LDL receptor-deficient mice

Abstract

Cardiovascular disease, largely because of disruption of atherosclerotic lesions, accounts for the majority of deaths in people with type 1 diabetes. Recent mouse models have provided insights into the accelerated atherosclerotic lesion initiation in diabetes, but it is unknown whether diabetes directly worsens more clinically relevant advanced lesions. We therefore used an LDL receptordeficient mouse model, in which type 1 diabetes can be induced at will, to investigate the effects of diabetes on preexisting lesions. Advanced lesions were induced by feeding mice a high-fat diet for 16 weeks before induction of diabetes. Diabetes, independently of lesion size, increased intraplaque hemorrhage and plaque disruption in the brachiocephalic artery of mice fed low-fat or high-fat diets for an additional 14 weeks. Hyperglycemia was not sufficient to induce plaque disruption. Furthermore, diabetes resulted in increased accumulation of monocytic cells positive for S100A9, a proinflammatory biomarker for cardiovascular events, and for a macrophage marker protein, without increasing lesion macrophage content. S100A9 immunoreactivity correlated with intraplaque hemorrhage. Aggressive lowering primarily of triglyceride-rich lipoproteins prevented both plaque disruption and the increased S100A9 in diabetic atherosclerotic lesions. Conversely, oleate promoted macrophage differentiation into an S100A9-positive population in vitro, thereby mimicking the effects of diabetes. Thus, diabetes increases plaque disruption, independently of effects on plaque initiation, through a mechanism that requires triglyceride-rich lipoproteins and is associated with an increased accumulation of S100A9-positive monocytic cells. These findings indicate an important link between diabetes, plaque disruption, and the innate immune system. intraplaque hemorrhage ͉ macrophage ͉ S100A9

Calgranulins May Contribute Vascular Protection In Atherogenesis

“…57 On the other hand, diabetes increased the accumulation of S100A9-positive monocytes in atherosclerosis in lowdensity lipoprotein (LDL) receptor-deficient (LDLR -/-) mice and S100A9 levels correlated with intraplaque hemorrhage, suggesting links between diabetes, plaque disruption and the innate immune system. 58 However, insulin resistance, macrophage accumulation and atherosclerosis were unaffected in LDLR -/-mice chimeras transplanted with S100A9 -/-bone marrow cells. 25 The prominence of neutrophils in atherosclerotic lesions of ApoE -/-mice, but of DC expressing S100A8/A9 in LDLR -/-lesions, could determine different disease courses.…”

Mechanisms of Urokinase Plasminogen Activator (uPA)-mediated Atherosclerosis

“…Therefore S100A8/A9 could mediate enhanced accumulation of both lipids and macrophages in lesions of SR-uPA ϩ/0 mice. S100A8/A9 are also associated with plaque rupture in both humans and diabetic mice (53,61), and older SR-uPA ϩ/0 mice have significantly increased plaque rupture (16). It will be interesting to generate SR-uPA ϩ/0 mice that are deficient in S100A8/A9 and test whether accelerated atherosclerosis and plaque rupture in SR-uPA ϩ/0 mice are dependent on S100A8/A9.…”

“…8), although the molecular pathways that lead from uPA expression to S100A8/A9 up-regulation remain to be defined. S100A8/A9 are excellent candidate mediators of accelerated atherosclerosis in SR-uPA mice and of uPA/Plg-mediated atherogenesis in humans because they are present in human and mouse lesions and are atherogenic in mice (53)(54)(55). S100A8/A9 potentially accelerate atherosclerosis via chemoattractant and proinflammatory activities that include binding to the RAGE and TLR4, activation of NF-B, and up-regulation of the adhesion molecule CD11b in circulating monocytes (56 -58).…”

Diabetes and atherosclerosis: is there a role for hyperglycemia?

“…One mouse model that has enabled studies of the effects of diabetes alone versus those of diabetes-induced hyperlipidemia is a transgenic LDL-receptor-deficient mouse in which type 1 diabetes can be induced by a virus (27,28). In this model, viral infection results in T-cell mediated destruction of pancreatic b?-cells expressing a viral protein transgene, closely mimicking the autoimmune destruction of these cells that occurs in type 1 diabetes in humans.…”