Mechanisms of cell signaling by nitric oxide and peroxynitrite: from mitochondria to MAP kinases.
Many of the biological and pathological effects of nitric oxide (NO) are mediated through cell signaling pathways that are initiated by NO reacting with metalloproteins. More recently, it has been recognized that the reaction of NO with free radicals such as superoxide and the lipid peroxyl radical also has the potential to modulate redox signaling. Although it is clear that NO can exert both cytotoxic and cytoprotective actions, the focus of this overview are those reactions that could lead to protection of the cell against oxidative stress in the vasculature. This will include the induction of antioxidant defenses such as glutathione, activation of mitogen-activated protein kinases in response to blood flow, and modulation of mitochondrial function and its impact on apoptosis. Models are presented that show the increased synthesis of glutathione in response to shear stress and inhibition of cytochrome c release from mitochondria. It appears that in the vasculature NO-dependent signaling pathways are of three types: (i) those involving NO itself, leading to modulation of mitochondrial respiration and soluble guanylate cyclase; (ii) those that involve S-nitrosation, including inhibition of caspases; and (iii) autocrine signaling that involves the intracellular formation of peroxynitrite and the activation of the mitogen-activated protein kinases. Taken together, NO plays a major role in the modulation of redox cell signaling through a number of distinct pathways in a cellular setting.
Levonen
A L
AL
Department of Pathology, University of Alabama at Birmingham, 35294-0019, USA.
Patel
R P
RP
Brookes
P
P
Go
Y M
YM
Jo
H
H
Parthasarathy
S
S
Anderson
P G
PG
Darley-Usmar
V M
VM
D000818:Animals; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009566:Nitrates / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D010084:Oxidation-Reduction; D015398:Signal Transduction / Q000502:physiology*
D009566:Nitrates; C039642:peroxynitric acid; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases