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

Abstract

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.