Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) typically carries a poor prognosis. Growing evidence indicates that overabundant production of nitric oxide (NO) may be responsible for a large part of the secondary injury that follows SAH. Although SAH modulates the activity of all three isoforms of nitric oxide synthase (NOS), the inducible isoform, NOS-2, accounts for a majority of NO-mediated secondary injuries after SAH. Here, we review the indispensable physiological roles of NO that must be preserved, even while attempting to downmodulate the pathophysiologic effects of NO that are induced by SAH. We examine the effects of SAH on the function of the various NOS isoforms, with a particular focus on the pathological effects of NOS-2 and on the mechanisms responsible for its transcriptional upregulation. Finally, we review interventions to block NOS-2 upregulation or to counteract its effects, with an emphasis on the potential therapeutic strategies to improve outcomes in patients afflicted with SAH. There is still much to be learned regarding the apparently maladaptive response of NOS-2 and its harmful product NO in SAH. However, the available evidence points to crucial effects that, on balance, are adverse, making the NOS-2/NO/peroxynitrite axis an attractive therapeutic target in SAH.

Keywords: Heparin; NOS-1; NOS-2; NOS-3; nitric oxide (NO); subarachnoid hemorrhage (SAH).

Figure 1

Inflammatory and ischemic cascades induced by subarachnoid hemorrhage that lead to NOS-2 upregulation. Subarachnoid hemorrhage (SAH) results in extravasation of large amounts of blood into the subarachnoid space. Erythrocytes lyse, releasing hemoglobin metabolites such as methemoglobin, heme and hemin, which act as TLR-4 ligands, activating NF-kB signaling, causing production of inflammatory cytokines, and upregulating NOS-2 expression. Aneurysmal rupture and vasospasm can cause transient cerebral ischemia, which upregulates HIF-1-dependent genes including NOS-2. Cerebral ischemia increases intracellular Ca²⁺ concentrations, activating calcineurin-NFAT signaling, which upregulates NOS-2. Upregulation of NOS-2 generates excess NO and peroxynitrite, which mediate significant bystander cellular injury. Several of these pathways are amenable to blockade or modulation, as illustrated