Role in cell death

Role of Nitric Oxide in Apoptosis

Nitric oxide (NO) is an important signaling molecule that acts in many tissues to regulate a diverse range of physiological processes including vasodilation, neuronal function, inflammation and immune function. Nitric oxide has also been demonstrated to be involved in the regulation of apoptosis.

The effects of apoptosis vary depending upon the dose of NO and the type of cell used and has been shown to be able to both induce apoptosis and to protect from apoptosis in different cell types. Nitric oxide has been demonstrated to inhibit apoptosis in a number of cell types including leukocytes, hepatocytes, trophoblasts and endothelial cells. Generally the anti-apoptotic effects of NO can be mediated through a number of mechanisms such as the nitrosylation and inactivation of many of the caspases including caspase 3, caspase 1 and caspase 8. Other mechanisms include activating p53, upregulating heat shock protein 70 (and consequently blocking recruitment of pro-caspase 9 to the Apaf-1 apoptosome), upregulating Bcl-2 and Bcl-XL (with subsequent inhibition of cytochrome C release from the mitochondria) and activating cGMP signaling leading to activation of cGMP-dependent protein kinases and suppression of caspase activity.

The effects of NO on apoptosis are generally classified as cGMP dependent or independent. Nitric oxide is able to activate cGMP signaling through the interaction of NO with the haem group of guanylate cyclase. The production of cGMP leads to the activation of cGMP-dependent protein kinases and possibly to increased expression of anti-apoptotic proteins. We are particularly interested in the anti-apoptotic effects of NO on endothelial cells and trophoblasts and are currently investigating the mechanism of action of NO in these cells.

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