ROS and RNS are capable of mediating gene and protein expression through the regulation of transcript factors (e.g., nuclear factor-xB and activator protein-1) and many additional mechanisms. Although it is beyond the scope of this chapter to describe or discuss all the intracellular signaling mechanisms involved in triggering gene expression, examples of recent hypotheses are considered in this section and illustrated in Figure 3. Both 02" and H202 activate tyrosine protein kinases, which subsequently stimulate MAP kinases and phospholipase Cy, and ultimately alter gene expression mediated by the activation of several transcription factors in the nucleus. Other recent theories suggest that Po2-sensitive proteins appear to contain specific regions called PAS domains. These regions are sites that potentially sense changes in or ROS formation. ROS
generation and lowering ofP02 modifies the configuration of PAS domains, which facilitate dimerization of the proteins and their translocation to the nucleus where they up-regulate gene expression. For example, HIF, a PAS protein, senses lowering of P02 or ROS, and it subsequently translocates into the nucleus and induces expression of the VEGF gene in pulmonary tissue (27, 28). The absence of HIF and VEGF results in development of a respiratory distress syndrome that leads to premature death of neonatal mice, and impairs the proliferation ofPASMC during hypoxia (5, 26). There is evidence that voltage-sensitive K+ channels also possess the PAS domain and, therefore, are able to detect changes (28). However, their roles in cell physiology during hypoxia have not yet been completely elucidated and needs further examination under conditions that promote PH.
Other examples of up-regulated gene expression by redox or ROS signaling are: adhesion proteins, antioxidant enzymes, NOS, receptors, and many respiratory adaptations to hypoxic environments. ROS and RNS can also influence the growth and death ofcells through a variety ofmechanisms. Cellular release of ROS is now know to serve as an intercellular messenger to stimulate proliferation via mechanisms common to natural growth factors. For example, growth factors appear to activate Akt/protein kinase B pathways through oxidant mechanisms and initiate cell division. 02'~ seems to mediate the downstream effects of Ras and Rac in non-phagocytic cells, and it contributes to the unchecked proliferation ofRas-transformed cells (15).
Recent evidence also indicates a role for 02" andH202 in the control ofVSM proliferation both in vitro and in vivo (10). As increased ROS production and PKC and MAPK are activated coincidentally in acute and chronically hypoxic pulmonary tissues, it might be appropriate to suggest a hypothesis that these pathways may converge to promote mitogenic activities leading to pulmonary vascular remodeling. Cytosolic Ca2+concentration is another critically important factor that controls cell proliferation and cell cycle progression of pulmonary cells (18). Thus, there is a possibility that changes in intracellular Ca2+ levels initiated by ROS in PASMC in hypoxic conditions might be involved in promoting cell proliferation and remodeling during progressive PH. Oxidative stress has been shown to mediate hormone-induced hypertrophy, and under some circumstances to induce apoptosis. Studies have indicated that apoptosis contributes to postpartum arterial remodeling in the neonatal lamb. Furthermore, it has been reported that apoptosis of VSM cells is regulated by p53-dependent and -independent pathways (36). Although the mechanisms involved in the oxidant-induced apoptosis of VSM cells are still not clearly understood, it is quite possible that K+ channels, which have been shown to promote apoptosis (18), could be one of the pathways that mediates apoptotic cell death of PASMC induced by ROS. Since overproduction of ROS and RNS triggers apoptotic cell death, ROS levels appear to be very critical in keeping a delicate balance between cell proliferation and apoptosis, a slight change in the ROS production may control vascular remodeling. For example, since K+ channels, which are regulated by ROS (32), promote apoptosis under normal circumstances, changes in ROS production and down-regulation of K+ channel or up-regulation of MAPK/JNK activities during hypoxia may in turn be a primary cause of cell proliferation and initiation of pulmonary artery remodeling leading to PH.
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