HIF-1 and human disease: one highly involved factor
This extract was created in the absence of an abstract.
Oxygen homeostasis represents an important organizing principle for human development and physiology. The essential requirement for oxidative phosphorylation to generate ATP is balanced by the risk of oxidative damage to cellular lipids, nucleic acids, and proteins. As a result, cellular and systemic O2concentrations are tightly regulated via short- and long-acting response pathways that affect the activity and expression of a multitude of cellular proteins (for review, seeSemenza 1999a). This delicate balance is disrupted in heart disease, cancer, cerebrovascular disease, and chronic obstructive pulmonary disease, which represent the most common causes of mortality and account for two-thirds of all deaths in the U.S. (Greenlee 2000). Appreciation of the fundamental importance of oxygen homeostasis for development, physiology, and disease pathophysiology is growing but still incomplete. Knowledge acquisition is presently exponential when one includes areas, such as the role of angiogenesis in ischemic or neoplastic disease, in which investigators are studying oxygen homeostasis even though they may not interpret their studies within this broad physiological context.
Vascular endothelial growth factor (VEGF) plays an essential role in angiogenesis (for review, seeFerrara and Davis-Smyth 1997;Ferrara 1999). The regulation of VEGF expression illustrates how reduced O2 availability (hypoxia) can elicit physiological responses via multiple molecular mechanisms. VEGF expression is induced when most cell types are subjected to hypoxia, thus providing a mechanism by which tissue perfusion can be optimized to demand. Steady state levels ofVEGF mRNA increase in hypoxic cells as a result of increased production (transcriptional activation) and decreased destruction (mRNA stabilization). Whereas overall protein synthesis is inhibited in response to hypoxia,VEGF mRNA is efficiently translated into protein by use of an internal ribosome entry site (Stein et al. 1998). Finally, expression of the VEGF receptor FLT-1 is also induced when endothelial cells are exposed to …
