dc.description.abstract | Abstract
Arsenite (As (III)) is a human carcinogen, also known to increase the risk of cardiovascular diseases, such as atherosclerosis and blackfoot disease. Heme oxygenase-1 (HO-1) is induced by a variety of agents, such as heme, oxidative stress, heat shock, cytokines, and some heavy metals (arsenite and cadmium). HO-1 catalyzes heme degradation into iron, biliverdin, and carbon monoxide. Biliverdin is subsequently converted to bilirubin by bilirubin reductase since bilirubin has antioxidant properties, HO-1 is considered to play a protective role against oxidative injury. In this thesis, how HO-1 is induced by low dose of sodium arsenite (< 1 ?M) in bovine aortic endothelial cells and human fibroblasts is investigated. To examine which pathway or signaling molecule involved in low dose sodium arsenite-mediated induction of HO-1, several inhibitors we were used adopted in this study. The results show that both adriamycin and actionmycin D decrease 1 ?M sodium arsenite-induced HO-1 expression, indicating that HO-1 expression induced by 1 ?M sodium arsenite is via transcription and translation. Pre-treatments of BAEC and HFW with Calphostin C (an inhibitor of protein kinase C), H8 and H89 (inhibitor of protein kinase A), quinacrine
(an inhibitor of phospholipase A2), BATPA/AM (an calcium chelater) reduce HO-1 expression levels by 1 ?M As (III). Unfortunately, quinacrine and BATPA/AM also inhibit RNA synthesis. The inhibitory effects of quinacrine and BATPA/AM on arsenite-induced HO-1 expression are unlikely due to inhibition of phospholipase A2 and calcium, respectively. Since other inhibitors of PKC family, such as bisindolylmaleimide I, D-erythio-sphingosine and chelerythrine chloride showed no effect on HO-1 induction by 1 ?M As (III), therefore Calphostin C is also not simply via PKC inhibition to decrease HO-1 expression. The present results imply that PKA is probably involved in low dose sodium arsenite-induced HO-1 expression in BAEC and HFW. However, further confirmation is required. | en_US |