8 1 Background
POX. An appropriate level of NO, therefore, allows the induction of antioxidant
enzymes for ROS scavenging, which enables the mitigation of chromosomal DNA
damage and compromise of telomere shortening. It is well known that the length
of telomeres is correlated with the lifespan of organisms from yeast to mammals
(Vera et al. 2013 ). Therefore, longer telomeres underlies extended lifespan.
• High-level NO behaves as an etiological initiator of tumor-like pathogenesis.
The inhibitory effect of high-level NO on O 2 binding to hemoglobin within red
blood cells interprets a preanoxic state occurring due to restricted O 2 supply to
blood vessel-dispersed tissues. In the case of low O 2 and long distance from the
capillary, the inhibition of mitochondrial and cellular O 2 uptake allows O 2 to further
diffuse away in the tissue (Poderoso et al. 1996 ). NO decreases the steepness of the
O 2 gradient in the preanoxic border, in which O 2 becomes a rate-limiting factor for
O 2 uptake by a low O 2 /NO ratio, gradually decreases O 2 uptake, and leaves O 2 to
reach cells that would be anoxic (Poderoso et al. 1996 ). The computational model
established by Thomas et al. ( 2001 ) has shown that a reversible inhibition of cellu-
lar O 2 uptake by NO substantially extends the zone of adequate tissue oxygenation
away from the blood vessel. However, when NO is overproduced due to pathogenic
infection and immune activation, a tumor-like angiogenesis and hyperplasia may
take place in the synovial tissues of joints. The thickened pannus with massive vas-
culatures and infiltrated lymphocytes was observed microscopically upon the histo-
chemical staining of synovial tissues (Bao et al. 2012 ; Wu et al. 2012 ).
• Interaction of NO with O 2 − promotes the nitrosylation/nitration and inac-
tivation of functional proteins. As the most potent oxidative reagents, RNS
may injure a wide array of biomolecules, including DNA and proteins, as well
as biomembranes. At a high level, NO readily reacts with O 2 − to give rise to
ONOO−. It is confirmed that ONOO− is responsible for the modification of pro-
teins by the S-nitrosylation of cysteine, 3-nitration of tyrosine, or other nitrosative
modifications. Our experimental data disclosed a correlation of high-level NO with
large-amount 3-nitrotyrosine (3NT) in mouse synovitis models (Gao et al. 2015 ).
This common modification occurring on a specific protein might cause a series of
unexpected changes: protein aggregation and subsequent biological responses; a
modulation of protein turnover; an alteration of signaling processes; and an induc-
tion of immunological responses (Trujillo et al. 2010 ). Besides, ONOO− can in
turn “uncouple” the original function of eNOS to let it becomes a O 2 −-generating
enzyme that contributes to vascular oxidative stress (Forstermann 2010 ). When the
flux of NO exceeds that of O 2 −, NO will react with ONOO−, resulting in the pre-
dominant formation of harmful NO 2 and N 2 O 3 (Thomas et al. 2010 ).
Overall, the threshold theory of NO-mediated disease and healthy effects addresses
a “double-edged sword” effect of NO on living cells, and helps to explain why
NO can repel the “foes” (pathogens) and also hurt the “friends” (autotissues).
Interestingly, this theory can be used to interpret the hormesis (low-dose toxin-
exiting) effect on the molecular level. For example, high-level NO and H 2 O 2 are
usually considered cytotoxic to living cells, but CR-mediated healthy effects are
dependent on both low-level NO and H 2 O 2. In turn, CR-induced NO triggers ROS