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Fig. 2.2 A scheme of two
signaling pathways initiated
by extracellular nucleotides
and adenosine, leading to
AMPK activation in EC
dependent upon adenosine uptake followed by the generation of intracellular AMP
that promotes activation of AMPK via LKB1. A scheme of these two pathways is
presented in Fig. 2.2. Extracellular nucleotides and adenosine whose local concen-
trations under pathophysiological conditions can be significantly increased, could
play an important role in maintaining cellular energy homeostasis by AMPK activa-
tion that modulates glucose uptake and fatty acid metabolism. We propose that P2Y
receptors and nucleoside transporters could be novel targets for a pharmacologi-
cal intervention to regulate AMPK and hence EC metabolism under pathological
conditions.
2.3.3 eNOS Activation by Extracellular Nucleotides
NO is an important signaling molecule regulating inflammation, angiogenesis and
thrombosis [74]. NO generated in the endothelium promotes vasorelaxation, pro-
tects ECs from apoptosis, inhibits vascular smooth muscle cell proliferation, blocks
platelet activation and enhances vascular growth. As such, NO maintains vascular
homeostasis. A decrease in NO production is implicated in endothelial dysfunction.
In ECs, NO synthesis requires the activation of eNOS. The expression and function
of eNOS is regulated at multiple levels: transcriptional, post-transcriptional (mRNA
stability) and post-translational (O-glycosylation, myristoylation, palmitoylation
and phosphorylation). Additional regulation occurs through eNOS dimerization and
interaction with regulatory proteins, such as calmodulin (CaM), caveolin-1 and heat-
shock protein 90 (HSP90), as well as eNOS subcellular targeting to caveolae, other
cellular membranes or the cytoplasm [40, 45].
Basal production of NO is maintained through allosteric activation of eNOS by
Ca 2+ /CaM, secondary to activation of phospholipase C gamma (PLC
), an increase
in [Ca 2+ ] i and activation of CaM. However, to reach high activity, eNOS has to
be phosphorylated at Ser-1177 [36]. Several kinases, including CaMKII, PI3K/Akt,
AMPK, ERK, p38 MAPK, PKC
γ
, and protein kinase A (PKA), have been reported
to phosphorylate Ser-1177 and thus activate eNOS [5, 14, 36, 81, 85, 102, 104,
116, 128].
α
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