Hyperglycemia and Endothelial Dysfunction in Atherosclerosis: Lessons from Type 1 Diabetes

Funk, Steven Daniel; Yurdagul, Arif; Orr, A. Wayne

doi:10.1155/2012/569654

Cited by 109 publications

(120 citation statements)

References 273 publications

(283 reference statements)

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“…Moreover, this accumulation plays a pathological role in the development of atherosclerosis by cross-linking collagen in vessel walls, producing stiffness of blood vessels, oxidizing low density lipoprotein and increasing inflammation through the receptor for AGE (RAGE) (Sims et al 1996, Zieman & Kass 2004. During AGE-mediated inflammatory responses, endothelial cells undergo a process of activation, characterized by enhanced cellular permeability and the up-regulation of leukocyte adhesion molecules (Funk et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Key structural and functional differences between early and advanced glycation products

Paradela-Dobarro

Rodiño-Janeiro

Alonso

et al. 2016

Journal of Molecular Endocrinology

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Most of the studies on advanced glycation end products (AGE) have been carried out with uncharacterized mixtures of AGE, so the observed effects cannot be linked to defined structures. Therefore, we analysed the structural differences between glycated human serum albumin (gHSA), a low glycated protein, and AGE-human serum albumin (AGE-HSA), a high glycated protein, and we compared their effects on endothelial functionality. Specifically, we characterized glycation and composition on both early and advanced stage glycation products of gHSA and AGE-HSA by using the MALDI-TOF-mass spectrometry assay. Furthermore, we studied the effects of both types of glycation products on reactive oxygen species (ROS) production and in the expression of vascular and intercellular cell adhesion molecules (VCAM-1 and ICAM-1) on human umbilical endothelial cells (HUVEC). We also measured the adhesion of peripheral blood mononuclear cells (PBMC) to HUVEC. Low concentrations of gHSA enhanced long-lasting ROS production in HUVEC, whereas lower concentrations of AGE-HSA caused the anticipation of the induced extracellular ROS production. Both gHSA and AGE-HSA up-regulated the expression of VCAM-1 and ICAM-1 at mRNA levels. Nevertheless, only AGE-HSA increased protein levels and enhanced the adhesion of PBMC to HUVEC monolayers. Functional differences were observed between gHSA and AGE-HSA, causing the latter an anticipation of the pro-oxidant effects in comparison to gHSA. Moreover, although both molecules induced genetic up-regulation of adhesion molecules in HUVEC, only the high glycated protein functionally increased mononuclear cell adhesion to endothelial monolayers. These observations could have important clinical consequences in the development of diabetic vascular complications.

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Section: Introductionmentioning

confidence: 99%

Key structural and functional differences between early and advanced glycation products

Paradela-Dobarro

Rodiño-Janeiro

Alonso

et al. 2016

Journal of Molecular Endocrinology

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“…Diabetes is widely regarded as an independent risk factor for the development of cardiovascular diseases, with ;80% of cardiovascular mortality and morbidity being linked to macrovascular complications, such as atherosclerosis (1)(2)(3). The increased risk of development of vascular complications in individuals with type 1 (T1D) or type 2 diabetes (T2D) occurs despite intensive glycemic control, stressing the need for novel approaches to lessen the burden of diabetes-mediated macrovascular injury (4).…”

mentioning

confidence: 99%

“…The vascular endothelium plays a crucial role in diabetesassociated atherosclerosis through the regulation of vessel permeability, inflammation, coordination of leukocyte trafficking, and thrombosis (1,5). Indeed, the function of the vascular endothelium is significantly impaired during diabetes, a phenomena termed endothelial dysfunction and characterized by the reduced bioavailability of an important endothelial cell mediator, nitric oxide (NO).…”

mentioning

confidence: 99%

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

et al. 2015

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Patients with diabetes have an increased risk of developing atherosclerosis. Endothelial dysfunction, characterized by the lowered bioavailability of endothelial NO synthase (eNOS)-derived NO, is a critical inducer of atherosclerosis. However, the protective aspect of eNOS in diabetes-associated atherosclerosis remains controversial, a likely consequence of its capacity to release both protective NO or deleterious oxygen radicals in normal and disease settings, respectively. Harnessing the atheroprotective activity of eNOS in diabetic settings remains elusive, in part due to the lack of endogenous eNOS-specific NO release activators. We have recently shown in vitro that eNOS-derived NO release can be increased by blocking its binding to Caveolin-1, the main coat protein of caveolae, using a highly specific peptide, CavNOxin. However, whether targeting eNOS using this peptide can attenuate diabetes-associated atherosclerosis is unknown. In this study, we show that CavNOxin can attenuate atherosclerotic burden by ∼84% in vivo. In contrast, mice lacking eNOS show resistance to CavNOxin treatment, indicating eNOS specificity. Mechanistically, CavNOxin lowered oxidative stress markers, inhibited the expression of proatherogenic mediators, and blocked leukocyte-endothelial interactions. These data are the first to show that endogenous eNOS activation can provide atheroprotection in diabetes and suggest that CavNOxin is a viable strategy for the development of antiatherosclerotic compounds.Diabetes is widely regarded as an independent risk factor for the development of cardiovascular diseases, with ;80% of cardiovascular mortality and morbidity being linked to macrovascular complications, such as atherosclerosis (1-3). The increased risk of development of vascular complications in individuals with type 1 (T1D) or type 2 diabetes (T2D) occurs despite intensive glycemic control, stressing the need for novel approaches to lessen the burden of diabetes-mediated macrovascular injury (4).The vascular endothelium plays a crucial role in diabetesassociated atherosclerosis through the regulation of vessel permeability, inflammation, coordination of leukocyte trafficking, and thrombosis (1,5). Indeed, the function of the vascular endothelium is significantly impaired during diabetes, a phenomena termed endothelial dysfunction and characterized by the reduced bioavailability of an important endothelial cell mediator, nitric oxide (NO). Such chronic attenuation of endothelial-derived NO release promotes platelet and leukocyte activation and adhesion, compromises endothelial cell barrier integrity, and causes the upregulation of proinflammatory genes (6-8). Moreover, reduced NO-dependent vasodilation and increased leukocyte adhesion to the endothelium, both of which are hallmarks of endothelial dysfunction, have been observed in patients with diabetes and diabetic animal models (9-12). Similarly, in cultured endothelial cells exposed to high glucose, lowered endothelial NO synthase (eNOS)-derived NO release was observed (13-15). In...

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“…CVD risk in patients with diabetes is likely to be increased via several interconnected factors, including infl ammation, endothelial dysfunction, and a prothrombotic state that result from a disturbed glucose metabolism (31)(32)(33). Our experiments show that diabetes increases MCP-1, ICAM-1, and SELE gene expression 2-to 3-fold in the aorta.…”

Section: Discussionmentioning

confidence: 62%

Diabetic atherosclerosis in APOE*4 mice: synergy between lipoprotein metabolism and vascular inflammation

Johnson

Kim

Knudson

et al. 2013

Journal of Lipid Research

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More than 10% of the United States adult population is estimated to have diabetes ( 1 ), and the leading cause of increased mortality in patients with diabetes is enhanced atherosclerosis ( 2, 3 ). A common cluster of harmful changes to lipoprotein metabolism, including increased plasma VLDL and LDL cholesterol, occurs in type-2 diabetic patients and is characterized by the presence of small, dense LDL particles, low HDL , increased triglycerides, and postprandial lipemia ( 4, 5 ). Serum lipid and lipoprotein levels in patients who have well-controlled type-1 diabetes are generally not higher than those in people without diabetes. However, hypertriglyceridemia and reduced HDL are common in poorly controlled patients, and plasma apoB100 levels, which indicate the number of LDL particles, correlate with glycemic control ( 5 ). This underscores the importance of diabetes-induced changes in lipoprotein composition and distribution as a cardiovascular disease (CVD) risk ( 4, 5 ), but how these relatively small changes in lipid metabolism that occur in the general human population lead to increased diabetic complications of atherosclerosis is not completely understood. Current animal models for atherosclerosis have not been able to address this issue satisfactorily, as they rely on gross lipid abnormalities, such as the lack of LDLR or apoE which cause severe hypercholesterolemia. Although modest increases in atherosclerosis have been observed when these hypercholesterolemic mice are made Abstract Diabetes is a major risk factor for cardiovascular disease. To examine how diabetes interacts with a mildly compromised lipid metabolism, we introduced the diabetogenic Ins2 C96Y/+ (Akita) mutation into mice expressing human apoE4 (E4) combined with either an overexpressing human LDL receptor gene (hLDLR) or the wild-type mouse gene. The hLDLR allele caused 2-fold reductions in plasma HDLcholesterol, plasma apoA1, and hepatic triglyceride secretion. Diabetes increased plasma total cholesterol 1.3-fold and increased apoB48 secretion 3-fold, while reducing triglyceride secretion 2-fold. Consequently, diabetic E4 mice with hLDLR secrete increased numbers of small, cholesterol-enriched, apoB48-containing VLDL, although they have near normal plasma cholesterol (<120 mg/dl). Small foam cell lesions were present in the aortic roots of all diabetic E4 mice with hLDLR that we analyzed at six months of age. None were present in nondiabetic mice or in diabetic mice without hLDLR. Aortic expression of genes affecting leukocyte recruitment and adhesion was enhanced by diabetes. ApoA1 levels, but not diabetes, were strongly correlated with the ability of plasma to effl ux cholesterol from macrophages. We conclude that the diabetes-induced proinfl ammatory changes in the vasculature and the hLDLR-mediated cholesterol accumulation in macrophages synergistically trigger atherosclerosis in mice with human apoE4, although neither alone is suffi cient.

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Hyperglycemia and Endothelial Dysfunction in Atherosclerosis: Lessons from Type 1 Diabetes

Cited by 109 publications

References 273 publications

Key structural and functional differences between early and advanced glycation products

Key structural and functional differences between early and advanced glycation products

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

Diabetic atherosclerosis in APOE*4 mice: synergy between lipoprotein metabolism and vascular inflammation

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