Regulation of Caspases by Nitric Oxide

Abstract

Nitric oxide can prevent or induce apoptosis depending on its concentration, cell type, and the oxidative milieu. Nitric oxide inhibits apoptosis and inflammation by S-nitrosylation of the active site cysteine of caspases, the central effector molecules of cell death as well as maturation of IL-1beta and IL-18. The ability of nitric oxide to S-nitrosylate caspases depends on multiple factors including the presence of free iron and intracellular redox potential. There are no known direct effects of nitric oxide on promoting caspase activation or activity. However, nitric oxide has been shown to promote apoptotic pathways in numerous cell types through the indirect activation of caspases. In this article we review the relationship of nitric oxide and caspase activity, modulation of this effect by iron, and clinical implications for the use of nitric oxide in regulating inflammation and apoptosis.

Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells

“…19,23,26 Our results show that staurosporine-induced reduction in eNOS activity was associated with caspasemediated cleavage of eNOS. Long-term (18-24 h) exposure of either eNOS-transfected COS-7 cells or BAECs to staurosporine resulted in a significant loss of eNOS protein and activity, an effect that was significantly reduced by caspase inhibitors.…”

“…18,19 There is increasing evidence that alterations in NO production affect signal transduction pathways that control apoptotic cell Samples of lysates from cells incubated as described were subjected to LDS-PAGE and immunoblotting followed by densitometry to quantify PARP protein levels, which is reported relative to the density of the 116-kDa band at zero time ¼ 1.0, or were assayed for caspase-3 activity, which is reported relative to that of untreated cells at zero time ¼ 1.0. Results shown were replicated in two independent experiments…”

“…16,17 NO can have either pro-or antiapoptotic effects in different types of cells, dependent on its concentration and the overall oxidative status of the cell, among other factors. [18][19][20] Antiapoptotic effects of NO have been attributed to its ability to inhibit the caspase cascade via reversible S-nitrosylation of key cysteine residues in various caspases. [20][21][22][23][24] Thus, eNOS-synthesized NO inhibited caspase-mediated apoptosis in endothelial cells; 23 it has been speculated that diminished production or availability of NO and enhanced apoptosis is related to susceptibility to atherosclerosis or age-related endothelial dysfunction.…”

Cell death, proliferation and repair in human myocarditis responding to immunosuppressive therapy

“…On follow-up biopsies of responders cell death decreased consistently, specifically by 68% for cell necrosis and 86% for cell apoptosis, allowing cell repair and proliferation to become effective biological events for the improvement of cardiac function. Several mechanisms may have concurred to cell rescue including: (a) removal of natural killer cells and activated T-lymphocytes that with their perforins and granzymes produce damage of myocyte membrane inducing cell necrosis and DNA fragmentation leading to apoptosis; 16,17 (b) Inhibition of cytokine and free radical production (particularly TNF-a and IL-1) that can activate intracellular caspase cascade and ultimately myocyte apoptosis; 18 (c) reduction of reactive oxygen species production (including NO), that at high levels can induce necrosis while at lower levels can trigger apoptosis; 19 (d) reduction of left ventricular load due to the improvement of cardiac dimensions and contractility. 20 It is noteworthy that even severe degrees of cell death can be remarkably slowed or stopped if the treatment is really able to interfere with the underlying mechanism of damage.…”

A novel CARD containing splice-isoform of CIITA regulates nitric oxide synthesis in dendritic cells

“…8A, CI-treatment upregulated the protein level of NOS2, thus indicating that NOS2 is a substrate for caspases. NO-donor (NONOate), which inhibits caspases-induced protein degradation, was utilized as positive control (Kim et al, 2002;Brüne, 2003;Huang et al, 2008).…”