Reactive oxygen species promote vascular smooth muscle cell proliferation.

D o reactive oxygen species play a role in the pathogen-esis of cardiovascular diseases? In 1992, Dr Berk and his group published an article that began to answer this question. During the following years, they performed a series of research projects that established the role of re-active oxygen species in vascular smooth muscle cell proliferation and cardiovascular diseases. It is now widely recognized that production of intracellu-lar reactive oxygen species (ROS) is substantially involved in the pathogenesis of cardiovascular diseases, in part by promoting vascular smooth muscle cell (VSMC) proliferation. However, 20 years ago, it was elusive why VSMCs proliferate in response to arterial injury. Thus, Dr Berk et al hypothesized that ROS generated during arterial injury could be a common mechanism involved. Using xanthine/xanthine oxidase to generate ROS, they were able to demonstrate that ROS stimulate VSMC proliferation in vitro and that H 2 O 2 was primarily responsible for xanthine/xanthine oxidase–induced VSMC DNA synthesis. 1 This Circulation Research article was the first milestone article that directly demonstrated the role of ROS in VSMC proliferation, triggering the studies that followed targeting the role of ROS in the pathogenesis of cardiovascular diseases. Until now, this article has been refer-enced by more than 450 articles. Three years later, they further reported that both O 2 − and H 2 O 2 stimulate VSMC growth but only O 2 − rapidly activates MAP kinase, suggesting that additional signal events are required for the mitogenic effects of H 2 O 2. 2 Based on these reports, it has been elucidated that the excess amount of ROS (oxidative stress) promotes VSMC proliferation and potentially develops cardiovascular diseases. In the subsequent 5 years, they focused on the interesting finding that ROS stimulates ERK1/2 in a biphasic manner in VSMCs. Finally, they demonstrated that one explanation for the delayed ERK1/2 activation was the response to the secreted oxidative stress–induced factors. 3 They analyzed the proteins released into the medium in response to ROS and found that cyclophilin A (CyPA) is one of the major secreted oxidative stress–induced factors. 4 Importantly, they demonstrated that human recombinant CyPA stimulates ERK1/2 and DNA synthesis in VSMCs in a concentration-dependent manner. 4 Thus, extracellular CyPA turned out to be a novel growth factor that contributes to ROS effects in VSMCs by promoting growth. Based on these reports, Dr Berk et al performed a series of studies demonstrating that changes in …