Regulation of cell proliferation by NADPH oxidase-mediated signaling: potential roles in tissue repair, regenerative medicine and tissue engineering.

The superoxide generating enzyme NADPH oxidase has received much attention as a major cause of oxidative stress underlying vascular disease. However, there is increasing evidence that oxidant signaling involving NADPH oxidase has other important roles in cell biology. Nox family proteins are the catalytic, electron-transporting subunits of the NADPH oxidase enzyme complex. It is now clear that reactive oxygen species (ROS) generated by NADPH oxidase participate in intracellular signaling processes that regulate cell differentiation and proliferation. These mechanisms are important in tissue repair and tumorigenesis, diverse conditions where cell proliferation is required, but when poorly controlled the generation of ROS is obviously detrimental. Indeed, NADPH oxidase-mediated cell proliferation has been observed in a wide range of cell types including those found in blood vessels, kidney, liver, skeletal muscle precursors, neonatal cardiac myocytes, lung epithelial cells, gastric mucosa, brain microglia, and a variety of cancer cells. NADPH oxidases act not as isolated elements downstream of a particular pathway, but rather may amplify multiple receptor tyrosine kinase-mediated processes by inhibiting protein tyrosine phosphatases. Therefore, NADPH oxidase-mediated redox signaling may represent a unique intracellular amplifier of diverse signaling pathways involved in tissue repair processes such as cell proliferation, wound healing, angiogenesis and fibrosis. Recent studies also suggest that NADPH oxidase is involved in differentiation of stem cells. As occurs in unresolved inflammation, however, hyperactivity of this enzyme system leads to tissue injury. Thus modulating NADPH oxidase may have significant impacts on regenerative medicine and tissue engineering, such as growing heart muscle.