Accelerated Atherosclerosis in Apoe(-/-) Mice Heterozygous for the Insulin Receptor and the Insulin Receptor Substrate-1
ABSTRACT Prediabetic states are associated with accelerated atherosclerosis, but the availability of mouse models to study connections between these diseases has been limited. The aim of this study was to test the selective role of impaired insulin receptor/insulin receptor substrate-1 signaling on atherogenesis.
To address the effects of impaired insulin signaling associated with hyperinsulinemia on atherosclerosis in the absence of obesity and hyperglycemia, we generated insulin receptor (Insr)/insulin receptor substrate-1 (Insr1) double heterozygous apolipoprotein (Apoe)-knockout mice (Insr(+/-)Irs1(+/-)Apoe(-/-)) mice. Insr(+/-)Irs1(+/-)Apoe(-/-) mice fed a Western diet for 15 weeks showed elevated levels of fasting insulin compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. There were no significant differences in glucose, triglyceride, HDL, VLDL, cholesterol levels or free fatty acid in the plasma of Insr(+/-)Irs1(+/-)Apoe(-/-) and Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Atherosclerotic lesions were increased in male (brachiocephalic artery) and female (aortic tree) Insr(+/-)Irs1(+/-)Apoe(-/-) compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Bone marrow transfer experiments demonstrated that nonhematopoietic cells have to be Insr(+/-)Irs1(+/-) to accelerate atherosclerosis. Impaired insulin signaling resulted in decreased levels of vascular phospho-eNOS, attenuated endothelium-dependent vasorelaxation and elevated VCAM-1 expression in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice. In addition, phospho-ERK and vascular smooth muscle cell proliferation were significantly elevated in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice.
These results demonstrate that defective insulin signaling is involved in accelerated atherosclerosis in Insr(+/-)Irs1(+/-)Apoe(-/-) mice by promoting vascular dysfunction and inflammation.
- SourceAvailable from: Catherine A Reardon
Article: Animal Models of Atherosclerosis[Show abstract] [Hide abstract]
ABSTRACT: Atherosclerosis is a chronic inflammatory disorder that is the underlying cause of most cardiovascular disease. Both cells of the vessel wall and cells of the immune system participate in atherogenesis. This process is heavily influenced by plasma lipoproteins, genetics, and the hemodynamics of the blood flow in the artery. A variety of small and large animal models have been used to study the atherogenic process. No model is ideal as each has its own advantages and limitations with respect to manipulation of the atherogenic process and modeling human atherosclerosis or lipoprotein profile. Useful large animal models include pigs, rabbits, and nonhuman primates. Due in large part to the relative ease of genetic manipulation and the relatively short time frame for the development of atherosclerosis, murine models are currently the most extensively used. Although not all aspects of murine atherosclerosis are identical to humans, studies using murine models have suggested potential biological processes and interactions that underlie this process. As it becomes clear that different factors may influence different stages of lesion development, the use of mouse models with the ability to turn on or delete proteins or cells in tissue specific and temporal manner will be very valuable.Arteriosclerosis Thrombosis and Vascular Biology 03/2012; 32(5):1104-15. DOI:10.1161/ATVBAHA.111.237693 · 5.53 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Context: Recent studies on mediators of inflammation, experimental models of atherosclerosis, and acute ischemia have identified novel mechanisms through which insulin may exert cardiovascular protective effects. This review aims to summarize current knowledge regarding the cardiovascular, antiinflammatory, and antiatherogenic effects of insulin, and the effect of intensive glycemic control in acute cardiovascular disease. Evidence Acquisition: Publications of interest were identified using preselected MeSH terminology and keywords to search online databases such as PubMed and OVID for the period January 1988 to February 2012. Relevant publications were obtained and reviewed by two independent observers, then evaluated a priori against the following criteria: study quality, main clinical outcomes, and applicability to clinical practice. Evidence Synthesis: Insulin has been shown to exert vasodilatory, antiinflammatory, and antiatherogenic effects in experimental models, independent of its glucose-lowering effects. Additionally, glucose is known to exert potent proinflammatory, prothrombotic, and proapoptotic effects during myocardial infarct, indicative that hyperglycemia is likely to be injurious to the heart. In this context, through its nonmetabolic and metabolic (glucose-lowering) effects, insulin is likely to be cardioprotective and to improve clinical outcomes in acute myocardial infarction. Conclusions: Despite promising experimental data and evidence of benefit from single-center randomized clinical trials, clinical evidence supporting the cardioprotective effects of insulin from a multicenter randomized clinical trial is still lacking. Future prospective studies with insulin infused at adequate concentrations, individually titrated to achieve and maintain euglycemia (blood glucose < 140 mg/dl) and minimize hypoglycemia, are required to investigate the role of insulin in the management of patients with acute cardiovascular disease.The Journal of Clinical Endocrinology and Metabolism 06/2012; 97(9):3079-91. DOI:10.1210/jc.2012-1112 · 6.31 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Impaired insulin signaling is central to development of the metabolic syndrome and can promote cardiovascular disease indirectly through development of abnormal glucose and lipid metabolism, hypertension, and a proinflammatory state. However, insulin's action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications of diabetes mellitus. Recent advances in our understanding of the complex pathophysiology of insulin's effects on vascular tissues offer new opportunities for preventing these cardiovascular disorders.Arteriosclerosis Thrombosis and Vascular Biology 09/2012; 32(9):2052-9. DOI:10.1161/ATVBAHA.111.241919 · 5.53 Impact Factor