The effect of hyperglycaemia on aortic endothelial and smooth muscle cell fate in hypoxia
Gao, Wei (2006) The effect of hyperglycaemia on aortic endothelial and smooth muscle cell fate in hypoxia. PhD thesis, Dublin City University.
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Diabetes, a metabolic disorder characterised by chronic hyperglycaemia due to relative insulin deficiency, insulin resistance or both, is associated with micro- and macro- vascular complications. Diabetes mellitus and impaired glucose tolerance are linked to increase cardiovascular morbidity and mortality. Endothelial and smooth muscle cells are the major factors in the development of cardiovascular diseases.
Both diabetes and hypertension have been shown to produce tissue hypoxia - a reduction in the normal level of tissue oxygen - that can occur from direct decreases in blood supply or from venous/arterial occlusion. Cellular responses to hypoxia include proliferation, angiogenesis, metabolism, apoptosis and migration. Therefore, we investigated the effects of hyperglycaemia on bovine aortic endothelial cell (BAEC) and bovine aortic smooth muscle cell (BASMC) growth (proliferation and apoptosis) under normoxic and hypoxic conditions.
Exposure of BAEC and BASMC to high glucose in media containing 10% fetal bovine serum (FBS) did not alter cell apoptosis and proliferation under normoxic conditions. Although serum deprivation (0.5% FBS containing media) significantly increased cell apoptosis and decreased cell proliferation under normoxic conditions, exposure to high glucose did not show any positive or negative effects. Mannitol, as controls for osmolarity, excluded the possibility of involvement of an osmotic effect on cells.
Hypoxia increased cell apoptosis and suppressed cell proliferation however; these effects on hypoxia-induced cell apoptosis and inhibition of proliferation were significantly reversed in the presence of high glucose.
The most evident response to hypoxia is via hypoxia-inducible factor 1 alpha (HIF-la). To investigate if hyperglycaemia modulated cell apoptosis and proliferation under hypoxic conditions through HIF-la; HIF-la expression was silenced following siRNA knockdown. Under these conditions, the hypoxia induced response was significantly impaired.
Taken together, these studies suggest that hyperglycaemia has no effect on BAEC and BASMC cell fate under normoxic conditions; hyperglycaemia impairs hypoxia-induced apoptosis and hypoxia-induced inhibition of cell proliferation under hypoxic conditions which is via a HIF-la-dependent mechanism.
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