Monomethylarsonous acid induced cytotoxicity and endothelial nitric oxide synthase phosphorylation in endothelial...

Chronic arsenic poisoning is reported to be associated with peripheral and cardiovascular disease, arteriosclerosis, Raynaud's syndrome, hypertension, and Blackfoot disease. Monomethylarsonous acid (MMA(III)) is a reactive metabolite of inorganic arsenic and a potent inhibitor of endothelial nitric oxide synthase (eNOS). Arsenic is also reported to phosphorylate eNOS in cultured keratinocyte and Human T cell leukemia Jurkat cells, respectively. In the present study, we examined the cytotoxicity and eNOS phosphorylation by MMA(III) exposure in cultured bovine aortic endothelial cells (BAEC). Results showed that MMA(III) is more toxic than arsenite in BAEC cells. The IC(50) values for MMA(III) and arsenite were determined to be approximately 1.7 and 24.1 micromol/L, respectively. Exposure of BAEC to MMA(III) (0.75 micromol/L) caused a significant eNOS phosphorylation 15 min after MMA(III) exposure. However, a complex of MMA(III) with dithiothreitol (DTT) that lacks the reactivity with vicinal thiols unaffected eNOS phosphorylation. The present study shows that MMA(III )generated during biomethylation of arsenic is highly toxic in BAEC. Our study also suggests that MMA(III) could induce the eNOS phosphorylation through modification to cellular thiols of the eNOS enzyme. And the initial up-regulation of eNOS phosphorylation by MMA(III )seems to be an adaptive response against disruption of eNOS bioactivity during arsenic exposure.