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Regulation of Endothelial Nitric Oxide Synthase Activity and Gene Expression
Author(s) -
WU KENNETH K.
Publication year - 2002
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2002.tb04062.x
Subject(s) - endothelial nitric oxide synthase , nitric oxide synthase , nitric oxide , gene expression , chemistry , nitric oxide synthase type iii , microbiology and biotechnology , atp synthase , regulation of gene expression , biochemistry , gene , enzyme , biology , enos , organic chemistry
A bstract : Endothelial nitric oxide synthase (eNOS) is constitutively expressed in endothelial cells lining the blood vessel and the heart. It plays a major role in vascular and tissue protection. Its activity is tightly controlled by an intramolecular autoinhibitory element that hinders calmodulin binding. This molecular hindrance is removed by elevated intracellular calcium levels. The catalytic activity of eNOS is augmented by phosphorylation of a C‐terminal serine residue (Ser‐1177 of human eNOS) through the phosphatidyl‐3 kinase (PI‐3K)/Akt pathway. Its activity is also enhanced by binding to heat shock protein‐90. These two processes are calcium independent. The two biochemical events appear to facilitate calmodulin access to its binding site. eNOS is upregulated at the transcriptional level. Its upregulation is mediated by an increased Sp1 binding to its cognate site on eNOS promoter/enhancer region via the action of protein phosphatase 2A (PP2A). PP2A is activated by a signaling pathway including PI‐3γ→ Janus activated kinase 2 (Jak2) → MEK‐1 → ERK1 and 2. The transcriptional and posttranslational enhancement of eNOS activity is two‐ to threefold above the basal level. A higher magnitude of augmentation of eNOS gene expression can be achieved by gene transfer, which confers protection against vascular diseases and ischemia‐induced tissue injury in experimental animals. These findings provide new insight into the protective role of eNOS and the therapeutic potential of eNOS gene therapy.