Biomedical Engineering Reference
In-Depth Information
markedly, but lack of glutathione reductase and TrxR1 heightens H
2
O
2
production
only slightly. In the absence of glutathione reductase, tetrahydrobiopterin supple-
mentation prevents increase in H
2
O
2
generation.
171
Asymmetric Dimethylarginine
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide
synthase. It is metabolized by dimethylarginine dimethylaminohydrolase DDAH1
and DDAH2 isoforms. Sterol response element-binding proteins — SREBP1c
repressor and SREBP2 activator — impede and promote transcription of the Ddah1
gene, respectively [
1110
].
9.10.3.3
Flow and Nitric Oxide Synthesis
Two signaling pathways can be involved in flow-mediated changes in NO
production. The initial, rapid, G-protein- and Ca
2
+
-dependent phase of NO
production depends on the rate of change of shear and not shear magnitude.
The subsequent lower rate, G-protein- and Ca
2
+
-independent NO production that
depends on shear magnitude, is involved in sustained NO release.
Wall shear stress, among other components of hemodynamic stress, regulates NO
release. Ca
2
+
response to WSS depends on
Ca
2
+
]
e
[
1111
]. Stepwise increase in
[
Ca
2
+
]
i
is associated with NO metabolism via a receptor-triggered signaling cascade.
Time gradient of wall shear stress yields a transient high-concentration burst
of NO release. Time gradient of WSS causes a NO-mediated sustained activation
of extracellular signal-regulated kinases ERK1 and ERK2 via G proteins [
1099
].
Low and high NO concentrations inhibit and activate ERK1 and ERK2 kinases,
respectively. These gradients also generate a persistent production of
reactive
oxygen species
that act independently and synergetically with NO to mediate
activation of ERK1 and ERK2 kinases.
Ca
2
+
]
i
[
1112
]. Mechanically modulated
wall shear stress transiently raises
[
[
Sirtuins
Pulsatile flow over cultured endothelial cells increases mitochondrial genesis as
well as the activity of sirtuin-1 (silent mating type information regulator; Vol. 2-
Chap. 2. Cell Growth and Proliferation) that functions as an NAD
+
-dependent
171
Tetrahydrobiopterin is a cofactor of the 3 aromatic amino acid hydroxylases used in the
degradation of phenylalanine and synthesis of neurotransmitters serotonin, melatonin, dopamine,
adrenaline, and noradrenaline, as well as nitric oxide. Tetrahydrobiopterin is a cofactor for
tryptophan, phenylalanine, and tyrosine hydroxylase, glyceryl ether monooxygenase, and nitric
oxide synthase.
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