Progression Of Atherosclerosis In Diabetes Research Articles

Potential Mechanisms and Effects of Chinese Medicines in Treatment of Diabetic Atherosclerosis by Modulating NLRP3 Inflammasome: A Narrative Review.

Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) is an intracellular sensor that detects endogenous danger signals and environmental irritants to assemble into the NLRP3 inflammasome. Activation of the NLRP3 inflammasome leads to the secretion of the proinflammatory cytokines interleutkin (IL)-1β and IL-18 and induces pyroptosis. Recent studies have shown that the NLRP3 inflammasome participates in the initiation and progression of diabetic atherosclerosis through pathological mechanisms such as β-cell dysfunction, insulin resistance, endothelial cell dysfunction, monocyte adhesion and infiltration, and smooth muscle cell proliferation and migration. In diabetic atherosclerosis, Chinese medicine has been proven effective for the inflammatory response mediated by the NLRP3 inflammasome. This review summarizes the latest progress on the NLRP3 inflammasome in the pathogenesis and potential Chinese medicine treatment of diabetic atherosclerosis.

Rosmarinic Acid Increases Macrophage Cholesterol Efflux through Regulation of ABCA1 and ABCG1 in Different Mechanisms.

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.

Paracrine Effects of Perivascular Adipose Tissue on Atherogenesis: Role of Extracellular Vesicles‐Mediated Intercellular Communications

Background Development of atherosclerosis depends on the interaction between various factors. Type 2 diabetes accelerates these interactions and predisposes to rapid progression of atherosclerosis. Diminution of vasoprotective effects of perivascular adipose tissue (PVAT) in metabolic disorders suggests a molecular link between diabetes and atherosclerosis. Objectives To assess the paracrine role of the PVAT on the progression of diabetic atherosclerosis, via intercellular communications between PVAT and the underlying vasculature. Methods Periaortic adipose tissue from Type 2 diabetic (db/db) mice were transplanted around the right common carotid arteries of ApoE-/- mice, followed by 16 weeks of atherogenic diet. Carotid arteries and adipose tissues were assessed for lesion formation and inflammatory markers, respectively. Adipose stem cells (ASCs) from PVAT were treated with lipopolysaccharide (1µg/ml), palmitate (200µM), and high-glucose (42 mM) for 24 hrs (denoted as P-ASCs) to mimic type 2 diabetes-associated metabolic alterations. Small extracellular vesicles (sEV) were isolated from the conditioned media. Aortic vascular smooth muscle cells (SMCs) were incubated with ASC-derived sEV (25µg/ml). The migratory potential of SMCs was evaluated by wound healing assay. Results Histological analysis displayed accelerated atherogenic plaque formation with transplantation of type 2 diabetic PVAT around the carotid arteries of ApoE-/- mice, which is otherwise resistant to plaque formation. Pro-inflammatory markers were significantly increased in periaortic adipose tissue from db/db compared to WT. sEV secreted from P-ASCs greatly enhanced the SMC migration when compared with the control ASCs. Conclusions Our data shows type 2 diabetes-accelerated progression of atherosclerosis is mediated by PVAT-derived sEV.

Role of NFAT in the Progression of Diabetic Atherosclerosis.

Nuclear factor of activated T cells (NFAT) is a transcription factor with a multidirectional regulatory function, that is widely expressed in immune cells, including cells in the cardiovascular system, and non-immune cells. A large number of studies have confirmed that calcineurin/NFAT signal transduction is very important in the development of vascular system and cardiovascular system during embryonic development, and plays some role in the occurrence of vascular diseases such as atherosclerosis, vascular calcification, and hypertension. Recent in vitro and in vivo studies have shown that NFAT proteins and their activation in the nucleus and binding to DNA-related sites can easily ɨnduce the expression of downstream target genes that participate in the proliferation, migration, angiogenesis, and vascular inflammation of vascular wall related cells in various pathophysiological states. NFAT expression is regulated by various signaling pathways, including CD137-CD137L, and OX40-OX40L pathways. As a functionally diverse transcription factor, NFAT interacts with a large number of signaling molecules to modulate intracellular and extracellular signaling pathways. These NFAT-centered signaling pathways play important regulatory roles in the progression of atherosclerosis, such as in vascular smooth muscle cell phenotypic transition and migration, endothelial cell injury, macrophage-derived foam cell formation, and plaque calcification. NFAT and related signaling pathways provide new therapeutic targets for vascular diseases such as atherosclerosis. Hence, further studies of the mechanism of NFAT in the occurrence and evolution of atherosclerosis remain crucial.

MicroRNA profiling of diabetic atherosclerosis in a rat model

ObjectiveThe incidence of diabetic atherosclerosis (DA) is increasing worldwide. The study aim was to identify differentially expressed microRNAs (DE-miRs) potentially associated with the initiation and/or progression of DA, thereby yielding new insights into this disease.MethodsMatched iliac artery tissue samples were isolated from 6 male rats with or without DA. The Affymetrix GeneChip microRNA 4.0 Array was used to detect miRs. Differential expression between atherosclerotic group and non-atherosclerotic group samples was analyzed using the Gene-Cloud of Biotechnology Information platform. Targetscan and miRanda were then used to predict targets of DE-miRs. Functions and pathways were identified for significantly enriched candidate target genes and a DE-miR functional regulatory network was assembled to identify DA-associated core target genes.ResultsA total of nine DE-miRs (rno-miR-206-3p, rno-miR-133a-5p, rno-miR-133b-3p, rno-miR-133a-3p, rno-miR-325-5p, rno-miR-675-3p, rno-miR-411-5p, rno-miR-329-3p, and rno-miR-126a-3p) were identified, all of which were up-regulated and together predicted to target 3349 genes. The target genes were enriched in known functions and pathways related to lipid and glucose metabolism. The functional regulatory network indicated a modulatory pattern of these metabolic functions with DE-miRs. The miR-gene network suggested arpp19 and MDM4 as possible DA-related core target genes.ConclusionThe present study identified DE-miRs and miRNA-gene networks enriched for lipid and glucose metabolic functions and pathways, and arpp19 and MDM4 as potential DA-related core target genes, suggesting DE-miRs and/or arpp19 and MDM4 could act as potential diagnostic markers or therapeutic targets for DA.

TUG1 promotes diabetic atherosclerosis by regulating proliferation of endothelial cells via Wnt pathway.

To explore the specific role of TUG1 in regulating the occurrence and progression of diabetic atherosclerosis and its underlying mechanism. TUG1 expressions in coronary artery disease (CAD) tissues, normal arterial tissues, endothelial cells induced by high-dose glucose and tumor necrosis factor-α (TNF-α) were detected by quantitative Real-time polymerase chain reaction (qRT-PCR). The effects of TUG1 on proliferation, migration and cell cycle of human umbilical vein endothelial cells (HUVECs) were detected by cell counting kit-8 (CCK-8), transwell assay and flow cytometry, respectively. Subsequently, protein expressions of proliferation-related genes, cell cycle-related genes and Wnt pathway-related genes were detected by Western blot after altering TUG1 expression in HUVECs. Further rescue experiments were carried out to explore whether TUG1 could regulate diabetic atherosclerosis via Wnt pathway. Overexpressed TUG1 was found in CAD tissues and endothelial cells induced by high-dose glucose and TNF-α compared with those of controls. TUG1 overexpression remarkably promoted proliferation, migration and cell cycle of HUVECs. Protein expressions of β-catenin and c-Myc were upregulated by overexpression of TUG1. Rescue experiments indicated that XAV-939, the inhibitor of Wnt pathway, could partially reverse the increased proliferative and migratory changes in HUVECs induced by TUG1 overexpression. We found that overexpressed TUG1 stimulates proliferation and migration of endothelial cells via Wnt pathway, thereby promoting the occurrence and progression of diabetic atherosclerosis.

Activated Status and Altered Functions of Neutrophils in Poorly Controlled Diabetes

Objectives. This study aimed to investigate the association of hyperglycemia and AGE on the phenotypes and biological functions of neutrophils to understand their roles in diabetes-related atherosclerosis. Methodology. Healthy subjects (HS) (n=5) and type 2 diabetic patients grouped according to glycemic control [good control, HbA1c 7% or less, n=6 (well controlled diabetic, WCD); poor control, HbA1c more than 9%, n=6 (poorly controlled diabetic, PCD)] were included in the study. Neutrophils were isolated from peripheral venous blood samples. To determine in vitro effects of high glucose and AGE, neutrophils derived from HS were exposed to 5 mM glucose, 25 mM glucose, 100 μg/mL BSA and AGE-BSA. We determined basal and PMA-stimulated production of ROS, expression of CD11b and CD66b, release of MPO, cell migration to IL-8 and adhesion to an endothelial cell layer. Results. In diabetic subjects, cells from WCD produced significantly higher basal and PMA-stimulated ROS ( p =0.014), while cells from PCD showed significantly increased expression of CD11b, CD66b and MPO production (p=0.021, 0.034, 0.05, respectively). The release of MPO was significantly increased after PMA stimulation in cells incubated in AGE-BSA, compared to those incubated in unmodified BSA. We observed significantly enhanced migration towards IL-8 and adherence to endothelial cells in neutrophils exposed to high glucose. Conclusions. Our findings indicate the activated status of neutrophils from diabetic patients. Neutrophils from healthy subjects exposed to conditions simulating hyperglycemia showed increased adhesive capacity. We made the novel finding of enhanced neutrophil migration toward IL-8 and adherence to endothelial cells upon exposure to high glucose conditions. These altered neutrophil functions may lead to the development and progression of atherosclerosis in diabetes.

Manganese supplementation reduces monocyte adhesion to endothelial cells by reducing ROS and downregulating ICAM‐1 independently of MnSOD

Manganese (Mn2+ ) levels have been found to be lower in the plasma and lymphocytes of diabetic patients and in the heart and aortic tissue of patients with atherosclerosis. Studies in our laboratory have shown that Zucker diabetic fatty rats (ZDF) supplemented with Mn2+ had lower cholesterol (25%, p<0.05), ICAM‐1 (17%, p<0.04), and higher adiponectin (38%, p<0.01) levels in blood. Cell culture studies with Human Umbilical Vein Endothelial Cells (HUVECs) showed that Mn2+ supplementation reduces adhesion of monocytes to endothelial cells (ECs). This study examines the mechanisms by which Mn2+ supplementation decreases monocyte adhesion to ECs, a key event in the development of atherosclerosis. HUVECs were treated with Mn2+ (0, 5, 10 μM) for 24 hours, then exposed to high glucose (HG, 25 mM) for another 24 hrs. Results demonstrate that Mn2+ supplementation decreases ICAM‐1 surface (20%, p<0.05) and total expression (65%, p<0.005), MCP‐1 secretion (16%, p<0.05), and ROS levels (21%, p<0.02) in HG‐treated HUVECs. Silencing studies using siRNA against MnSOD showed that similar effects of Mn2+ on ICAM‐1 expression and ROS were observed in MnSOD knockdown HUVECs. This study suggests that Mn2+ supplementation can decrease monocyte adhesion to ECs, and thereby delay progression of atherosclerosis in diabetes, by decreasing ROS, MCP‐1 secretion, and ICAM‐1 expression, independently of MnSOD.Grant Funding Source: NIDDK and Office of Dietary Supplements

Rosuvastatin Blocks Advanced Glycation End Products-elicited Reduction of Macrophage Cholesterol Efflux by Suppressing NADPH Oxidase Activity via Inhibition of Geranylgeranylation of Rac-1

Adenosine triphosphate-binding membrane cassette transporter A1 (ABCA1) and ABCG1 play a crucial role in macrophage cholesterol efflux, which is a novel therapeutic target for atherosclerosis. Advanced glycation end products (AGE) and their receptor RAGE axis is involved in accelerated atherosclerosis in diabetes as well. However, the role of AGE-RAGE axis in macrophage cholesterol efflux is not fully understood. We examined here whether AGE-RAGE axis could impair cholesterol efflux from human macrophage cells, THP-1 cells by suppressing ABCA1 and ABCG1 expression. We further investigated the effects of rosuvastatin on cholesterol efflux from AGE-exposed THP-1 cells. AGE increased reactive oxygen species generation in THP-1 cells, which was completely inhibited by rosuvastatin, anti-RAGE-antibody or diphenylene iodonium chloride (DPI), an inhibitor of NADPH oxidase. The antioxidative effect of rosuvastatin on AGE-exposed THP-1 cells was significantly prevented by geranylgeranyl pyrophosphate (GGPP). AGE decreased ABCA1 and ABCG1 mRNA levels, and subsequently reduced cholesterol efflux from THP-1 cells, which was prevented by GGPP. DPI mimicked the effects of rosuvastain. The results demonstrated that rosuvastatin could inhibit the AGE-induced reduction of THP-1 macrophage cholesterol efflux by suppressing NADPH oxidase activity via inhibition of geranylgeranylation of Rac-1. Our present study provides a novel beneficial aspect of rosuvastatin in diabetes; rosuvastain may prevent the development and progression of atherosclerosis in diabetes by not only reducing serum cholesterol level, but also by improving cholesterol efflux from foam cells of the arterial wall via blocking the harmful effects of AGE on macrophages.

Cardiovascular disease in recent onset diabetes mellitus

Diabetes is associated with a marked increased risk of atherosclerotic vascular disorders, including coronary, cerebrovascular, and peripheral artery disease. Cardiovascular disease (CVD) could account for disabilities and high mortality rates in patients with diabetes. Conventional risk factors, including hyperlipidemia, hypertension, smoking, obesity, lack of exercise, and a positive family history, contribute similarly to macrovascular complications in type 2 diabetic patients and non-diabetic subjects. The levels of these factors in diabetic patients are certainly increased, but not enough to explain the exaggerated risk for macrovascular complications in the diabetic population. Furthermore, recently, macrovascular complications of diabetes have been shown to start before the onset of diabetes. Indeed, several clinical studies have confirmed the increased risk of CVD in patients with impaired glucose tolerance (IGT). Since insulin resistance-related postprandial metabolic derangements are thought to play a central role in the development and progression of CVD in patients with IGT, amelioration of postprandial metabolic disturbance is a therapeutic target for the prevention of CVD in these high-risk patients. Therefore, in this paper, we review the molecular mechanisms for the increased risk of CVD in recent onset diabetes mellitus, especially focusing on postprandial dysmetabolism. We also discuss here the potential therapeutic strategies that specially target the mechanisms responsible for vascular alterations in diabetes.

Dual Blockade of the Renin-Angiotensin System in Diabetic Nephropathy

The accelerated progression of atherosclerosis in diabetes is most probably the end result of the cumulative impact of the major risk factors that are more prevalent in diabetic subjects, namely obesity and dyslipidemia, the derangement in carbohydrate metabolism (hyperglycemic environment, hyperinsulinism, and insulin resistance), a prothrombotic tendency, and, perhaps most important, microalbuminuria and hypertension (1–5). At least two additional cardiovascular risk factors are probably more pronounced in diabetes; they are endothelial dysfunction (6) and an inflammatory reaction in the affected blood vessels mediated by the proinflammatory interleukins and expressed by elevated levels of C-reactive protein (7). Microalbuminuria is often the first clinical manifestation of early microvascular derangement. In type 2 diabetes, it is the hallmark of subsequent diabetic nephropathy and a surrogate marker of cardiovascular disease and increased cardiovascular mortality (8). Furthermore, the presence of microalbuminuria predicts a worse outcome after percutaneous coronary intervention. The 2-year mortality after percutaneous coronary intervention in diabetic patients with microalbuminuria was increased by 85% compared with individuals with normal urinary albumin excretion (9). Microalbuminuria is associated with echocardiographic evidence of left ventricular hypertrophy and identifies overall cardiovascular risk also in hypertensive nondiabetic patients (10,11). It is therefore mandatory to screen all diabetic as well as nondiabetic hypertensive patients for the presence of microalbuminuria. Indeed, all the relevant professional associations have included annual screening for microalbuminuria in their recommendations (12,13). Treatment strategies aimed at reducing urinary albumin excretion were found to be effective in retarding the progression of renal disease, as manifested by prolongation of the time to doubling of serum creatinine and postponement of end-stage renal disease and the need to renal replacement therapy (14–17). Furthermore, the magnitude of early decline in albuminuria in response to a given therapeutic intervention is a reliable predictor …

Evidence Supporting a Role for Endoplasmic Reticulum Stress in the Development of Atherosclerosis in a Hyperglycaemic Mouse Model

We previously observed a correlation between elevated levels of vascular endoplasmic reticulum (ER) stress and accelerated atherosclerotic plaque development in chronically hyperglycemic apolipoprotein-deficient (ApoE(-/-)) mice. We hypothesize that ER stress plays a causative role in diabetic atherogenesis. Here we examine the temporal relation between the onset of hyperglycemia, glucosamine accumulation in the vessel wall, ER stress, and the development of atherosclerosis. We demonstrate, by using streptozotocin-induced hyperglycemic ApoE(-/-) mice, that conditions of hyperglycemia increase intracellular glucosamine levels and endothelial ER stress levels in the endothelium before the onset of atherosclerosis. At 15 weeks of age, hyperglycemic mice have significantly larger atherosclerotic lesions (0.120 +/- 0.023 vs. 0.065 +/- 0.021 mm2; p = 0.001) relative to normoglycemic mice. Significantly, hyperglycemia-associated accelerated atherosclerosis is observed before the onset of dyslipidemias, suggesting that leveled glucose is sufficient to promote atherogenesis independently. Diagnostic markers of elevated ER-stress levels are increased in macrophage-derived foam cells in early and advanced atherosclerotic lesions. Dietary supplementation with valproate, a small branched-chain fatty acid that interferes with ER-stress signaling, significantly attenuates accelerated atherogenesis in this model. Together, these data are consistent with a causative role for hyperglycemia-associated ER stress in the development and progression of diabetic atherosclerosis.

Expanding expression of the 5-lipoxygenase/leukotriene B 4 pathway in atherosclerotic lesions of diabetic patients promotes plaque instability

Emerging evidence now indicates that the 5-lipoxygenase (5-LO) pathway play a role in the pathogenesis of atherosclerosis and restenosis. The expression of 5-LO by activated macrophages in symptomatic plaques leads to leukotriene B 4 (LTB 4) accumulation and enhanced synthesis and release of matrix metalloproteinases (MMPs) that can promote plaque rupture. However, the role of 5-LO pathway in diabetic vascular disease has not been previously reported. Thus, the present study was designed to analyze the expression of 5-LO in carotid plaques of diabetic patients and to investigate the possible role of 5-LO pathway in the pathogenesis and progression of diabetic atherosclerosis. Atherosclerotic plaques from 60 patients undergoing carotid endarterectomy were divided into non-diabetic and diabetic group. Plaques were analyzed for 5-LO, MMP-2 and MMP-9 by immunohistochemical, Western blot, and densitometric analyses, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+macrophages, CD3+T-lymphocytes, and HLA-DR+inflammatory cells. LTB 4 were quantified by enzyme-linked immunosorbent assay. 5-LO showed abundant immunoreactivity in human atherosclerotic carotid lesions, and was colocalized with macrophage infiltrates in atherosclerotic intima. 5-LO expression was higher in diabetic compared with non-diabetic plaques and was associated with increased MMP-2 and MMP-9 expression. Follow-up analyze with zymography assay revealed MMP activity was elevated in diabetic compared with non-diabetic plaques. Notably, in contrast to non-diabetic plaques, LTB 4 levels were significantly increased in diabetic plaques by enzyme-linked immunosorbent assay. These results suggest that overexpression of 5-LO and LTB 4 in atherosclerotic plaques possibly promote MMP-induced plaque rupture in diabetes. Hence, anti-LTs may be useful, not only in reducing atherogenesis, but also in the prevention and treatment of acute atherothrombotic events in diabetic patients.

Cilostazol reduces inflammatory burden and oxidative stress in hypertensive type 2 diabetes mellitus patients

Objectives Inflammation and oxidative stress cause genesis and progression of atherosclerosis in diabetes. This study aimed to assess effects of Cilostazol on these factors in hypertensive type 2 diabetic patients. Materials and methods In randomized, open, add-on preventive controlled clinical trial design, 60 hypertensive type 2 diabetics aged ≥45 years were evaluated clinically and for total leukocyte count, erythrocyte sedimentation rate, serum albumin, serum hsC-reactive protein, plasma malondialdehyde, blood reduced glutathione and HbA1c levels. After informed consent, 30 patients received Cilostazol (100 mg) twice daily orally as add-on therapy. At 1 month follow-up, 26 patients in control group and 22 patients in Cilostazol group completed the trial and particular parameters were re-evaluated. Results The mean age and duration of diabetes were 55 ± 7 years and 8 ± 6 years, respectively. At follow-up, the Cilostazol group showed significant ( p < 0.001) decrease in hsC-reactive protein (23.6%), erythrocyte sedimentation rate (38.7%), total leukocyte count (12.6%), plasma malondialdehyde (17.6%), HbA1c (0.17%, p = 0.002) and increase in serum albumin (11.9%), blood reduced glutathione (3.5%) from baseline. UKPDS 10 years risk of coronary heart disease decreased by 6% ( p = 0.002). The control group did not show significant improvement in inflammatory profile, oxidative status and HbA1c. Conclusion Inflammatory and oxidative stress is high in hypertensive type 2 diabetic patients. Cilostazol reduces these factors as well as coronary heart disease risk in diabetes mellitus.

Novel inhibitors of glycation and AGE formation

Accelerated formation of advanced glycation/lipoxidation and endproducts (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several natural and synthetic compounds have been proposed and tested as inhibitors of AGE/ALE formation. We have previously reported the therapeutic effects of several new AGE/ALE inhibitors on the prevention of nephropathy and dyslipidemia in streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the effects of various concentrations of a compound, LR-90, on the progression of renal disease and its effects on AGE and receptor for AGE (RAGE) protein expression on the kidneys of diabetic STZ-rats. Diabetic male Sprague-Dawley rats were treated with or without LR-90 (0, 5, 20, 25, and 50 mg/l of drinking water). After 32 weeks, body weight, glycemic status, renal function, and plasma lipids were measured. Kidney histopathology and AGE/ALE accumulation and RAGE protein expression in tissues were also determined. In vitro studies were also performed to determine the possible mechanism of action of LR-90 in inhibiting AGE formation and AGE-protein cross-linking. LR-90 protected the diabetic kidneys by inhibiting the increase in urinary albumin-to-creatinine ratio and ameliorated hyperlipidemia in diabetic rats in a concentration-dependent fashion without any effects on hyperglycemia. LR-90 treatment also reduced kidney AGE/ALE accumulation and RAGE protein expression in a concentration-dependent manner. In vitro, LR-90 exhibited general antioxidant properties by inhibiting metal-catalyzed reactions and reactive oxygen species (OH radical) and reactive carbonyl species (methlyglyoxal, glyoxal) generations without any effect on pyridoxal 5' phosphate. The compound also prevents AGE-protein cross-linking reactions. These findings demonstrate the bioefficacy of LR-90 in treating nephropathy and hyperlipidemia in diabetic animals by inhibiting AGE accumulation, RAGE protein expression, and protein oxidation in the diabetic kidney. Additionally, our study suggests that LR-90 may be useful also to delay the onset and progression of diabetic atherosclerosis as the compound can inhibit the expression of RAGE and inflammation-related pathology, as well as prevent lipid peroxidation reactions.

Soluble Tumor Necrosis Factor Receptor 2 Is Independently Associated With Brachial-Ankle Pulse-Wave Velocity in Nonobese Japanese Type 2 Diabetic Patients

Type 2 diabetes is associated with high mortality and morbidity due to atherosclerosis. Biermen (1) estimated that typical risk factors, including blood pressure, cholesterol, and smoking, can account for no more than 30% of excess cardiovascular risk factor in diabetic patients. Thus, other factors seem to play a role in the progression of atherosclerosis in diabetes. Aortic stiffness measured by pulse- wave velocity (PWV) is shown to be highly predictive of cardiovascular mortality in type 2 diabetic patients (2). While age and blood pressure are shown …

Soluble Tumor Necrosis Factor Receptor 1 Is Strongly and Independently Associated With Serum Homocysteine in Nonobese Japanese Type 2 Diabetic Patients

The major clinical consequence of type 2 diabetes is mortality and morbidity from atherosclerotic vascular disease. With regards to the risk factors responsible for the evolution of atherosclerosis, Bierman (1) estimated that typical risk factors, including smoking, cholesterol, and blood pressure, can account for no more than 30% of excess cardiovascular risk factors in diabetic patients. Thus, other factors seem to play a key role in the progression of atherosclerosis in diabetes. One potential factor is homocysteine. Homocysteine has been shown …

Arterial intimal retention of pro-atherogenic lipoproteins in insulin deficient rabbits and rats

Recent observations that remnants of triglyceride rich lipoproteins become trapped within the subendothelial of arterial vessels gives rise to the possibility that these particles could initiate the atherogenic cascade. Increased frequency and progression of atherosclerosis in diabetes might in part be a consequence of raised concentrations in plasma of remnant lipoproteins. In addition, diabetes may lead to changes in the arterial vasculature which exacerbate arterial retention of pro-atherogenic lipoproteins. To explore these possibilities, in this study we determined aortic retention of chylomicron remnants, which are of intestinal origin, and of hepatically derived low-density lipoproteins (LDL) in insulin deficient rabbits and rats. The two species were selected because of their disparate susceptibility to develop atherosclerosis in the presence of diabetes induced hyperlipidemia. Chylomicron remnants and LDL were differentially radiolabelled with a residual marker and injected simultaneously into conscious rabbits or rats. Arterial retention was determined 2 h after injection, and relative retention was expressed as a percentage of mean arterial exposure. We found in insulin deficient rabbits and rats that intimal and medial retention of chylomicron remnants was positively related to the degree of hyperglycemia and was significantly greater than in non-diabetic control groups. In contrast, insulin deficiency did not influence arterial retention of LDL. Rabbits which are susceptible to diabetes induced atherogenesis had significantly greater intimal retention of chylomicron remnants compared to rats. Results from this study support the hypothesis that chronic hyperglycemia promotes arterial retention of triglyceride rich remnant lipoproteins and that atherosclerotic susceptibility might be related to degree of remnant entrapment within the subendothelial space. Greater retention of remnant lipoproteins could in part explain the increased prevalence of atherogenesis in diabetes.