Hyperhomocyst(e)inemia and Endothelial Dysfunction in IDDM

Hofmann, M.; Kohl, B.; Zumbach, M.; Borcea, V.; Bierhaus, Angelika; Henkels, M.; Amiral, Jean; Fiehn, W.; Ziegler, Reinhard; Wahl, Peter; Nawroth, Peter P.

doi:10.2337/diacare.21.5.841

Cited by 146 publications

(104 citation statements)

References 52 publications

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“…Several studies have demonstrated that Hcy levels are increased in diabetes. Elevated Hcy levels were shown to be a stronger risk factor in diabetics than in non-diabetic patients (1,19,20,21,24,29,30). Plasma Hcy levels were also found to be significantly elevated in our type 2 diabetic patients with atherosclerotic vascular disease when compared with patients without vascular disease.…”

Section: Discussionmentioning

confidence: 49%

“…Hcy levels were found to be elevated in patients with vascular disease and were proposed to contribute to atherosclerosis in patients with coronary artery disease, stroke, and peripheral vascular disease (1,19,20,22,24,28). Hcy-induced vascular pathologies include fragmentation of the internal elastic lamina, disruption of elastic fibers, smooth muscle hyperplasia, and arterial and venous thrombosis (28).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated that plasma Hcy levels are elevated in diabetic patients (18)(19)(20)(21)(22)(23)(24). But the relation of inflammatory activity to Hcy levels is not well established.…”

Section: Introductionmentioning

confidence: 99%

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Relation of plasma homocysteine levels to atherosclerotic vascular disease and inflammation markers in type 2 diabetic patients

Akalın¹,

Alataş²,

Çolak³

2008

European Journal of Endocrinology

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Objective: Both hyperhomocysteinemia and increased inflammatory activity are shown to be associated with atherosclerosis. The relation of inflammatory activity to homocysteine (Hcy) levels is not well established. In the present study, we aimed to evaluate the relation of plasma Hcy levels to atherosclerotic vascular disease and inflammatory activity in type 2 diabetic patients. Design and methods: In total 90 type 2 diabetic patients were included in the study. Of these patients, 41 had established atherosclerotic vascular disease and 49 had no evidence of atherosclerotic vascular disease. Hcy levels and markers of inflammation, namely C-reactive protein, fibrinogen, erythrocyte sedimentation rate, interleukin-6, and tumor necrosis factor a (TNFa), were measured. Glucose regulation, C-peptide, lipid parameters, and renal functions were also studied. Results: Both Hcy levels and inflammation markers were all significantly elevated in patients with atherosclerotic vascular disease when compared with patients without vascular disease. Reduced renal functions were responsible for the majority of Hcy elevation in patients with vascular disease. Also, renal functions were significantly associated with both Hcy levels and inflammatory markers. There was no correlation between Hcy levels and inflammation markers except for TNFa. Conclusions: Inflammatory activity and Hcy levels are increased in type 2 diabetic patients with atherosclerotic vascular disease. Impairment of renal functions is the key factor that affects both Hcy levels and inflammation markers. Inflammation is not involved in the process by which Hcy leads atherosclerosis in type 2 diabetes.European Journal of Endocrinology 158 47-52

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

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Relation of plasma homocysteine levels to atherosclerotic vascular disease and inflammation markers in type 2 diabetic patients

Akalın¹,

Alataş²,

Çolak³

2008

European Journal of Endocrinology

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“…Other risk factors have been recognized, one of them is elevated level of homocysteine [3]. Increasing incidence of vasculopathy and preeclampsia in diabetes mellitus is associated with increased homocysteine level [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Retinopathy in pregnancy in women with type 1 diabetes - a study of associations with arterial wall elasticity and mutation in coagulation genes

Lauszus¹,

Grøn²,

Tjessem³

et al. 2017

Integr Obesity Diabetes

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Aim: The arterial wall elasticity and genetic setting is a potential risk factor for dysfunction of vas¬cular endothelial cells and the clinical expression of retinopathy. The prevalence was evaluated of polymorphism in the genes of methylene-tetrahydro-folate-reductase (MTFHR), Factor V, glycoprotein IIb/IIIa (Gp2b3a), and prothrombin in a cohort of pregnant women with type 1 diabetes. The role of hyperhomo¬cysteinemia in microangiopathy in diabetes mellitus has been debated and is mainly seen with reduced activity of the MTHFR gene. The arterial resistance index (AASI) has been used to detect arterial dysfunction and correlate with cardiovascular morbidity and mortality in patients with hypertension.Design: Two-hundred-and-thirty-three women with type 1 diabetes mellitus were analyzed for MTHFR gene polymorphism and Factor V Leiden. In 176 of these women AASI was further evaluated. In a sub-cohort of 40 women with preeclampsia, mutations in glycoprotein IIb/IIIa (Gp2b3a) and prothrombin was measured. The pregnancy and ophthalmological examination data charts were reviewed retrospectively.Results: Retinopathy was associated with higher AASI during pregnancy (p<0.01, in all three trimesters) and preeclampsia (p<0.05). The stiffness increased with higher grades of retinopathy. AASI in women with simplex and proliferative retinopathy followed different patterns during the three trimesters, even when adjusted for age, BMI, and glycemic regulation (p<0.01). None of the studied coagulation genes (MTHFR, Factor V, Gp2b3a, and prothrombin) were found associated with retinopathy or preeclampsia. Conclusion:Retinopathy showed a strong association with AASI during pregnancy and not outside pregnancy in women with type 1 diabetes. This suggests a pregnancy-related functional change in the vascular bed.A common polymorphism in methylene-tetrahydro-folate-reductase (MTFHR 677C>T, a C to T substitution at nucleotide 677, which converts alanine to a valine residue) has been identified as responsible for reduced MTHFR activity and increased plasma homocysteine [10,11].Factor V Leiden is a mutated form of human factor V that causes an increase in blood clotting. With this mutation, the anticoagulant protein secreted is inhibited, leading to an increased tendency to form dangerous, abnormal blood clots. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst ethnic Europeans and linked with increased risk of preeclampsia, abortions, intrauterine growth restriction, placental abruption, and thrombosis [12][13][14].Glycoprotein IIb/IIIa (Gp2b3a, also known as integrin αIIbβ3) is a complex found on platelets. It is a receptor for fibrinogen and von Lauszus FF (2017) Retinopathy in pregnancy in women with type 1 diabetes -a study of associations with arterial wall elasticity and mutation in coagulation genes

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“…1 Several aminothiols, including homocysteine and cysteine, can promote atherogenesis by virtue of their effects on endothelial function, vascular smooth muscle cell activation and hemostatic activation. [2][3][4][5][6][7][8] These aminothiols have a critical role as intracellular redox buffers, and it is also becoming increasingly recognized that they comprise an important extracellular redox system. 9,10 It has also been reported that homocysteine exerts its detrimental effects in part through a mechanism involving oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Homocysteine-induced oxidative stress upregulates chymase in mouse mastocytoma cells

et al. 2009

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Reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ), O À 2 and OH participate in the pathogenesis of ischemia/ reperfusion injury, inflammation and atherosclerosis. Our previous studies have suggested that increased angiotensin II (Ang II)-forming chymase may be involved in the development of atherosclerosis. However, the regulatory mechanism of chymase expression has not yet been clarified. In this study, we tested whether oxidative stress upregulates mouse mast cell proteinase chymase, mouse mast cell proteinase (MMCP)-5 or MMCP-4. We also examined the expression and activity of these proteins after treatment. Cultured mouse mastocytoma cells (MMC) displaying chymase-dependent Ang II-forming activity were treated with H 2 O 2 and several aminothiols with or without anti-oxidants. The levels of MMCP-5 and MMCP-4 expression were determined by quantitative RT-PCR; the level of chymase-dependent Ang II-forming activity was measured by high performance liquid chromatography using Ang I as a substrate. Treatment of MMC with homocysteine (0.1-3 mmol l -1 ) significantly increased MMCP-5 and MMCP-4 expression, as well as Ang II-forming activity. These effects were significantly inhibited by the addition of catalase and further suppressed by the combination of catalase and superoxide dismutase. Incubation with hydrogen peroxide alone caused a significant increase in Ang II-forming activity, which was completely suppressed by co-treatment with catalase. Furthermore, MMCP-5 and MMCP-4 expression levels were drastically suppressed and chymase induction by homocysteine was diminished under the GATA-inhibited condition. Homocysteine increased mast cell chymase expression and activity through the mechanism of oxidative stress. Our results suggest that there is a biochemical link between oxidative stress and the local Ang IIforming system.

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Hyperhomocyst(e)inemia and Endothelial Dysfunction in IDDM

Abstract: Hyperhomocyst(e)inemia is common in nephropathic diabetic patients and may contribute to the enhanced morbidity and mortality from cardiovascular diseases characteristically observed in IDDM patients with diabetic nephropathy.

Cited by 146 publications

References 52 publications

Relation of plasma homocysteine levels to atherosclerotic vascular disease and inflammation markers in type 2 diabetic patients

Relation of plasma homocysteine levels to atherosclerotic vascular disease and inflammation markers in type 2 diabetic patients

Retinopathy in pregnancy in women with type 1 diabetes - a study of associations with arterial wall elasticity and mutation in coagulation genes

Homocysteine-induced oxidative stress upregulates chymase in mouse mastocytoma cells

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