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Abstract

Hyperglycaemia is implicated in microvascular inflammatory injury and subsequent cardiac injury/dysfunction. Leucocyte adhesion to the endothelium, migration into tissue and toxic metabolite release are early critical steps. Taurine is a semi-essential amino acid that is endothelial protective and restrains excess leucocyte activity by the formation of less toxic inflammatory mediators. The aim was to establish if taurine reduces acute hyperglycaemia-induced endothelial cell apoptosis and leucocyte interactions and associated cardiac abnormalities. Male Sprague-Dawley rats (190-250 g) were randomised to control, hyperglycaemia, and hyperglycaemia plus taurine pre-treated groups. Taurine was gavaged (200 mg/kg body weight) for 5 days. Intravenous hyperglycaemia was established which was 4 times that of baseline for the 3-hour experiment. Using intravital microscopy, mesenteric post-capillary venules were examined for leucocyte rolling, adhesion and migration every 30 min from baseline. Endothelial cell apoptosis and intracellular adhesion molecule (ICAM-1) expression were assessed. In a separate experiment, blood pressure, pulse rate, cardiac injury marker (troponin T), cardiac tissue injury and oedema were also assessed. Hyperglycaemia significantly increased leucocyte adhesion and migration. Blood pressure and troponin T were also elevated significantly. Taurine prevented these cardiac changes, endothelial cell apoptosis and ICAM-1 expression. Taurine may have a therapeutic role in reducing diabetic microvascular inflammatory injury and concomitant cardiac dysfunction. Copyright (c) 2007 S. Karger AG, Basel.

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Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death.

J Kajstura, F Limana, B Safai … (2001)

To determine whether enzymatic p53 glycosylation leads to angiotensin II formation followed by p53 phosphorylation, prolonged activation of the renin-angiotensin system, and apoptosis, ventricular myocytes were exposed to levels of glucose mimicking diabetic hyperglycemia. At a high glucose concentration, O-glycosylation of p53 occurred between 10 and 20 min, reached its peak at 1 h, and then decreased with time. Angiotensin II synthesis increased at 45 min and 1 h, resulting in p38 mitogen-activated protein (MAP) kinase-driven p53 phosphorylation at Ser 390. p53 phosphorylation was absent at the early time points, becoming evident at 1 h, and increasing progressively from 3 h to 4 days. Phosphorylated p53 at Ser 18 and activated c-Jun NH(2)-terminal kinases were identified with hyperglycemia, whereas extracellular signal-regulated kinase was not phosphorylated. Upregulation of p53 was associated with an accumulation of angiotensinogen and AT(1) and enhanced production of angiotensin II. Bax quantity also increased. These multiple adaptations paralleled the concentrations of glucose in the medium and the duration of the culture. Myocyte death by apoptosis directly correlated with glucose and angiotensin II levels. Inhibition of O-glycosylation prevented the initial synthesis of angiotensin II, p53, and p38-MAP kinase (MAPK) phosphorylation and apoptosis. AT(1) blockade had no influence on O-glycosylation of p53, but it interfered with p53 phosphorylation; losartan also prevented phosphorylation of p38-MAPK by angiotensin II. Inhibition of p38-MAPK mimicked at a more distal level the consequences of losartan. In conclusion, these in vitro results support the notion that hyperglycemia with diabetes promotes myocyte apoptosis mediated by activation of p53 and effector responses involving the local renin-angiotensin system.

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Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat.

Dario Giugliano, Antonio Ceriello, Lisa Quagliaro … (2002)

This study investigated coronary perfusion pressure, nitric oxide (NO) and superoxide production, nitrotyrosine (NT) formation, and cardiac cell apoptosis in isolated hearts perfused with high glucose concentration. Coronary perfusion pressure; NO and superoxide anion generation; immunostaining for NT, inducible NO synthase (iNOS), and the constitutive type of NO synthase (NOS) eNOS; iNOS and eNOS mRNA expression by Western blot and RT-PCR; and apoptosis of cardiac cells were studied in hearts perfused for 2 h with solutions containing D-glucose at a concentration of 11.1 mmol/l (control), D-glucose at the concentration of 33.3 mmol/l (high glucose), or D-glucose (33.3 mmol/l) plus glutathione (0.3 mmol/l). Perfusion of isolated hearts in conditions of high glucose concentration caused a significant increase of coronary perfusion pressure (P < 0.001) and an increase of both NO and superoxide generation. However, superoxide production was 300% higher than baseline, whereas NO production was 40% higher (P < 0.001 for both). This effect was accompanied by the formation of NT, and an increase of iNOS expression. eNOS remained unchanged. At the end of the experiments, cardiac cell apoptosis was evident in hearts perfused with high glucose. The effects of high glucose were significantly prevented by glutathione. This study demonstrates that high glucose for 2 h is enough to increase iNOS gene expression and NO release in working rat hearts. Upregulation of iNOS and raised NO generation are accompanied by a marked concomitant increase of superoxide production, a condition favoring the production of peroxynitrite, a powerful pro-oxidant that can mediate the toxic effects of high glucose on heart by itself and/or via the formation of nitrotyrosine, as suggested by the detection of cell apoptosis.