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.

Mechanisms and therapeutic implications of RTA 408, an activator of Nrf2, in subarachnoid hemorrhage–induced delayed cerebral vasospasm and secondary brain injury

“…Increasing evidence has suggested that excess production of nitric oxide (NO) may contribute significantly to CV secondary to SAH [7]. Although SAH regulates the activity of all three isoforms of nitric oxide synthase (NOS), the inducible isoform iNOS accounts for most of the NO-mediated secondary damage after SAH [7]. Our study found SAH increased protein iNOS and it treatment with RTA 408 resulted in Fig 4. ELISA assay for TNF-alpha.…”

“…Prior to this study, the pathophysiology underlying SAH-induced CV and secondary brain injury was unclear and adequate strategies for treating it were elusive. Increasing evidence has suggested that excess production of nitric oxide (NO) may contribute significantly to CV secondary to SAH [7]. Although SAH regulates the activity of all three isoforms of nitric oxide synthase (NOS), the inducible isoform iNOS accounts for most of the NO-mediated secondary damage after SAH [7].…”

“…CV develops once SAH activates the inflammatory cascade [27]. The inflammation contributes to the upregulation of iNOS following SAH through its activation of one or more transcriptional pathwayssuch as NF-κB, hypoxia-inducible factor 1 (HIF-1), and the nuclear factor of activated T-cells (NFAT) [7]. NF-κB binds with its inhibitor, an enhancer in B-cell inhibitor (IκB) in the cytosol of cells.…”

“…Apoptosis in the vasculature is reported to play a significant role in SAH, and apoptotic cascades may be responsible for vasospasm [4,5] Therefore, the occurrence of apoptosis after SAH has important implications for both vasospasm and the long-term sequelae of SAH [6]. Furthermore, there is increasing evidence that oxidative stress and inflammation may be the leading causes of subarachnoid hemorrhage (SAH)-induced cerebral vasospasm and secondary brain injury [7].…”

Cerebral nitric oxide and mitochondrial function in patients suffering aneurysmal subarachnoid hemorrhage—a translational approach

“…In contrast, iNOS is highly upregulated in the presence of inflammatory stimuli in immune cells and neurons, causing detrimental effects by inducing cerebral vasospasm and microthrombus formation [ 18 , 28 , 32 , 33 , 36 , 38 ]. The activity of iNOS can be elevated due to ischemia-mediated activation of hypoxia-inducible factor (HIF)-1a pathway and inflammatory pathways induced by the extravasated blood [ 14 , 49 ]. Upregulated iNOS generates excessive amounts of NO, which accounts for a majority of NO-mediated secondary injuries after SAH [ 14 ].…”