Oxidative stress induced pulmonary endothelial cell proliferation is not mediated by superoxide

Cellular hyper-proliferation, endothelial dysfunction and oxidative stress are hallmarks of the pathobiology of pulmonary hypertension. Indeed, pulmonary endothelial cells proliferation is susceptible to redox state modulation. Some studies suggest that superoxide stimulates endothelial cell proliferation while others have linked the proliferative response to an up-regulation of peroxynitrite in lungs under oxidative stress. Given the divergence of opinion on the subject, it is important to establish the agents mediating cellular hyper-proliferation under oxidative stress. Using the combination of xanthine and xanthine oxidase, the current study demonstrates that neither superoxide nor hydrogen peroxide stimulated pulmonary endothelial cell proliferation. Alone, low level superoxide (100 RLU/s) did not alter DNA synthesis in endothelial cell and high concentration (500 RLU/s) superoxide decreased DNA synthesis to 31.8±3%, 30.4±2%, and 53.8±5% control at 0.1, 0.5 and 2.5% basal growth stimulation, respectively. Nonetheless, the formation of peroxynitrite under this condition stimulated proliferation to 49.2±9%, 51.1±8% and 71.2±2%, respectively. Taken together, pulmonary endothelial cell proliferation occurred only under conditions producing nitric oxide and superoxide in concert.

Keywords
Oxidative stress; superoxide; endothelial cells; peroxynitrite; proliferation