Superoxide counteracts low-density lipoprotein-induced human aortic smooth muscle cell proliferation

Previously, we demonstrated that the level of intracellular O2− is increased by low-density lipoprotein (LDL) in human aortic smooth muscle cells (HASMCs). The exact role of O2− in the LDL-induced proliferation of HASMCs, however, has not been determined. In this study, we found that the increase in the concentrations of intracellular O2− induced by native and oxidized LDL increased SMC-nitric oxide (NO) uptake rate. Moreover, the treatment of HASMCs with diethyldithiocarbamate (DETC), a superoxide dismutase inhibitor, significantly increased NO uptake rate owing to the increase in intracellular O2− concentrations. Although native and oxidized LDL decreased soluble guanylyl cyclase (sGC) protein content, they still caused a net increase in cyclic GMP production in HASMCs. In addition, when cyclic GMP production was normalized by sGC protein content and NO uptake rate, it was found to be positively dependent on the level of intracellular H2O2. Finally, we simulated cell proliferation stimulated by native and oxidized LDL as a linear function of intracellular O2− and H2O2 concentrations, demonstrating that O2− negatively modulated the native and oxidized LDL-stimulated HASMC proliferation through the increase in NO uptake rate.