Endothelial cell dysfunction and the pathogenesis of diabetic macroangiopathy

Laight, David W; Carrier, Martin; Änggård, Erik

doi:10.1002/(sici)1520-7560(199907/08)15:4<274::aid-dmrr46>3.0.co;2-g

Cited by 71 publications

(23 citation statements)

References 158 publications

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“…tients with diabetic mellitus, and endothelial cell dysfunction is an early marker of such complications (15). Previous in vitro studies have confirmed that exposure of human endothelial cells to high glucose induces significant alterations in cell growth and cell death (3,17,22).…”

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confidence: 99%

High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase

McGinn¹,

Saad²,

Poronnik³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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The mitogen-activated protein (MAP) kinases contribute to altered cell growth and function in a variety of disease states. However, their role in the endothelial complications of diabetes mellitus remains unclear. Human endothelial cells were exposed for 72 h to 5 mM (control) or 25 mM (high) glucose or 5 mM glucose plus 20 mM mannitol (osmotic control). The roles of p38 and p42/44 MAP kinases in the high glucose-induced growth effects were determined by assessment of phosphorylated MAP kinases and their downstream activators by Western blot and by pharmacological inhibition of these MAP kinases. Results were expressed as a percentage (means Ϯ SE) of control. High glucose increased the activity of total and phosphorylated p38 MAP kinase (P Ͻ 0.001) and p42/44 MAP kinase (P Ͻ 0.001). Coexposure of p38 MAP kinase blocker with high glucose reversed the antiproliferative but not the hypertrophic effects associated with high-glucose conditions. Transforming growth factor (TGF)-␤1 increased the levels of phosphorylated p38 MAP kinase, and p38 MAP kinase blockade reversed the antiproliferative effects of this cytokine. The high glucose-induced increase in phosphorylated p38 MAP kinase was reversed in the presence of TGF-␤1 neutralizing antibody. Although hyperosmolarity also induced antiproliferation (P Ͻ 0.0001) and cell hypertrophy (P Ͻ 0.05), there was no change in p38 activity, and therefore inhibition of p38 MAP kinase had no influence on these growth responses. Blockade of p42/44 MAP kinase had no effect on the changes in endothelial cell growth induced by either high glucose or hyperosmolarity. High glucose increased p42/44 and p38 MAP kinase activity in human endothelial cells, but only p38 MAP kinase mediated the antiproliferative growth response through the effects of autocrine TGF-␤1. High glucose-induced endothelial cell hypertrophy was independent of activation of the MAP kinases studied. In addition, these effects were independent of any increase in osmolarity associated with high-glucose exposure. high glucose; endothelial cell; growth; p38 mitogen-activated protein kinase; p42/44 mitogen-activated protein kinase; transforming growth factor-␤1

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confidence: 99%

High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase

McGinn¹,

Saad²,

Poronnik³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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“…We have proposed that oxidative stress precedes endothelial dysfunction and the subsequent development of insulin resistance [6,7]. Oxidative stress was assessed by measurement of plasma F 2 -isoprostanes (F 2 -IPs), which are prostaglandin-like molecules produced by the free radical-catalysed peroxidation of arachidonic acid [8].…”

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Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians with impaired glucose metabolism

et al. 2001

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Type II (non-insulin-dependent) diabetes mellitus is characterised by insulin resistance, pancreatic betacell defect, hypertension, dyslipidaemia and central obesity, and is recognised as part of a cluster of cardiovascular risk factors generally known as the Metabolic Syndrome [1]. The Indian Ocean island of Mauritius recently provided the background for a longitudinal epidemiological study (1987±1998) which is now seen as an indicator of the potential global impact of Type II diabetes [2,3]. Mauritius has a multiethnic population of 1.2 million, including people of Asian Indian (66 %), mixed European-African-Indian (31 %) and Chinese (3 %) descent. In 1987, the agestandardised prevalence of Type II diabetes in adults aged 30 years or more was 14.3 %, increasing to Diabetologia (2001) Abstract Aims/hypothesis. To measure oxidative stress, endothelial dysfunction and insulin resistance in Indian Mauritians at different stages of development of Type II (non-insulin-dependent) diabetes mellitus. Methods. Plasma total 8-epi-PGF 2a , an indicator of oxidative stress, was determined in age-matched subjects with normal glucose metabolism (n = 39), impaired glucose tolerance (n = 14), newly diagnosed diabetes (n = 8) and established diabetes (n = 14). Plasma glucose and insulin were measured at baseline and 2 h following an oral glucose tolerance test. Endothelial function was assessed by non-invasive digital pulse wave photoplethysmography. Results. Plasma 8-epi-PGF 2a increased in subjects with impaired glucose tolerance (p < 0.05) compared with control subjects, and was even higher in newly diagnosed diabetic patients (p < 0.01) and established (p < 0.01) diabetic patients. A tendency towards reduced endothelial function in subjects with impaired glucose tolerance became significant in patients with newly diagnosed and established diabetes (p < 0.01), and was correlated with 8-epi-PGF 2a (r = 0.36, p < 0.01). Insulin resistance (homeostasis model assessment) did not change in subjects with impaired glucose tolerance compared with control subjects, but increased in newly diagnosed (p < 0.01) and established (p < 0.001) diabetic subjects. The 8-epi-PGF 2a was correlated with fasting glucose (r = 0.50, p < 0.001), triglycerides (r = 0.40, p < 0.001) and insulin resistance (r = 0.35, p < 0.001). Conclusion/interpretation. Oxidant stress is an early event in the evolution of Type II diabetes and could precede the development of endothelial dysfunction and insulin resistance. [Diabetologia (2001) 44: 706± 712

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“…8 Increasing evidence suggests that endothelial dysfunction may play a central role in the development of atherosclerosis. 9 Endothelial dysfunction is characterized by inhibited vasodilation, increased vascular smooth-muscle proliferation, increased thrombogenesis, and proatherogenic cellular processes. 10 Abnormal endothelium-dependent vasodilation also occurs in the microcirculation of diabetic patients, where it may contribute to ischemia and its sequelae.…”

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Preventing Cardiovascular Complications of Type 2 Diabetes: Focus on Lipid Management

Henry¹

2001

Clinical Diabetes

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P revention of cardiovascular complications of diabetes must be considered a national public health goal in light of the increasing prevalence of the disease and the high frequency and seriousness of its complications. According to current estimates, more than 13 million people in the United States have physician-diagnosed diabetes, and another 5.4 million may have undiagnosed diabetes. 1 Recent figures from the Centers for Disease Control and Prevention (CDC) confirm that the prevalence of diabetes is growing at an alarming rate. For example, among people in their 30s, there was a 70% increase from 1990 to 1998. In this same time period, the prevalence of diabetes increased 33% among people of all ages and ethnic groups. Prevalence of diabetes varies to some degree by sex and ethnicity. Among people who are 20 years of age or older, diabetes occurs somewhat more commonly in white men than in white women (4.7% of women, 5.4% of men). Conversely, the disease affects women more frequently than men among African Americans (9.5% of women, 7.6% of men), Mexican Americans (11.4% of women, 8.1% of men), and American Indians/Alaska Natives (12% of women, 9.7% of men). Remarkably, the mortality rate among African-American men and women is at least twice that of whites. 1 Diabetes is well recognized as an independent risk factor for cardiovascular disease (CVD) in men and women. 3CVD is up to four times more common in people with diabetes than in those 113

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Endothelial cell dysfunction and the pathogenesis of diabetic macroangiopathy

Cited by 71 publications

References 158 publications

High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase

High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase

Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians with impaired glucose metabolism

Preventing Cardiovascular Complications of Type 2 Diabetes: Focus on Lipid Management

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