First 11 pages of thesis. - OPUS - Universität Würzburg

Several physiological situations like shear stress and exercise training increase
eNOS expression 89 . Transforming growth factor-β (TGF-β) and tumor necrosis
factor-α (TNF-α) influence eNOS mRNA levels. While TGF-β induces eNOS
mRNA and protein expression as well as enzyme activity 90 , TNF-α down
regulates eNOS expression 91 .
The activity of eNOS is regulated by a number of mechanisms including
post translational modification, mediating sub cellular localization of the
enzyme 92, 93 . Hormones like estrogen, catecholamines, vasopressin and platelet
derived mediators such as serotonins increase eNOS function. The activity of
eNOS is also determined by signaling complexes which are composed of the
enzyme and a conglomerate of adaptor proteins, structural proteins, kinases,
phosphatases and potentially proteins which affect association and determine
intracellular localization. The kinases and phosphatases phosphorylate and
dephosphorylate eNOS at various sites resulting in activation or attenuation of
the enzyme. For example, eNOS phosphorylation at Ser1177 activates eNOS
whereas phosphorylation at Thr495 attenuates eNOS activity. It was shown that
protein kinase C (PKC) promotes both the dephosphorylation of Ser1177 and
the phosphorylation at Thr495, resulting in attenuated enzymatic activity 94 . In
contrast cAMP dependent protein kinase (PKA) signaling leads to eNOS
phosphorylation at Ser1177 and dephosphorylation at Thr495 resulting in
activation of the enzyme 94 . In addition to the modulation by phosphorylation,
protein-protein interactions also influence eNOS activity. Further, post
translational modifications like N-terminal acylation, specifically myristoylation
and palmitoylation determines the sub cellular localization of the enzyme. The
modification targets eNOS to both the plasmalemmal vesicles, caveolae and the
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